DE69520282T2 - PYRROLO [2,3-D] PYRIMIDINE DERIVATIVES AND THEIR USE - Google Patents

Abstract

PCT No. PCT/EP95/03536 Sec. 371 Date Mar. 19, 1997 Sec. 102(e) Date Mar. 19, 1997 PCT Filed Sep. 8, 1995 PCT Pub. No. WO96/10028 PCT Pub. Date Apr. 4, 1996The invention relates to the use of the compounds mentioned below in the therapeutic treatment of tumor diseases and other proliferative diseases, such as psoriasis, and to novel compounds of that type. The compounds are compounds of formula I n is not 0, R is one or more substituents selected from halogen, alkyl, trifluoromethyl and alkoxy; and R1 and R2 are each independently of the other alkyl, or phenyl that is unsubstituted or substituted by halogen, trifluoromethyl, alkyl or by alkoxy, it also being possible for one of the two radicals R1 and R2 to be hydrogen, or R1 and R2 together form an alkylene chain having from 2 to 5 carbon atoms that is unsubstituted or substituted by alkyl; or salts thereof. Compounds of formula I inhibit protein kinases, for example the tyrosine protein kinase of the receptor for the epidermal growth factor, EGF.

Description

The invention relates to compounds of formula I

wherein

R₁ represents phenyl which is unsubstituted or substituted by one or two substituents from the group consisting of lower alkyl, halogen lower alkyl, (hydroxy- or lower alkanoyloxy) lower alkyl, lower alkoxy lower alkyl, (hydroxy-, lower alkoxy or lower alkanoyloxy) lower alkoxy lower alkyl, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino) lower alkoxy lower alkyl, (amino- or lower alkanoylamino) lower alkyl, lower alkylamino lower alkyl, di-lower alkylamino lower alkyl, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl) lower alkyl, (imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl or pyrrolyl) lower alkyl, (hydroxy-, lower alkoxy- or Lower alkanoyloxy)-lower alkylamino-lower alkyl, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkylamino-lower alkyl, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkylamino-lower alkyl, (imidazolyl-, triazolyl-, pyridyl-, pyrinidinyl- or pyrrolyl)- lower alkylamino-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, (amino-, lower alkylamino- l-di-lower alkylamino- or lower alkanoylamino)-lower alkyl-(thio-, sulfinyl- or sulfonyl)- lower alkyl, carboxy-lower alkyl, Lower alkoxycarbonyllower alkyl, aminocarbonyllower alkyl, N-lower alkylaminocarbonyllower alkyl, N,N-dilower alkylaminocarbonyllower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, C₁-C₃ Alkylenedioxy, phenyl lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkoxy, (amino- or lower alkanoylamino)-lower alkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy, (piperidinyl- piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkoxy, (imidazolyl- triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkylamino-lower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkylamino-lower alkoxy, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkylamino-lower alkoxy, (Inüdazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkylamino-lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkoxylower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoyloxy)-lower alkoxylower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylantno)-lower alkyl(thio-, suffinyl- or sulfonyl)-lower alkoxy, hydroxysulfonyllower alkoxy, carboxylower alkoxy, lower alkoxycarbonyllower alkoxy, aminocarbonyllower alkoxy, N-lower alkylaminocarbonyllower alkoxy, N,N-dini ederalkylaminocarbonyllower alkoxy, amino, lower alkylamino, dilower alkylamino, lower alkanoylamino, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolyl, triazolyl, pyridyl, pyrinüdinyl, pyrrolyl, mercapto, lower alkyl-(thio, sulfinyl or sulfonyl), (hydroxy, lower alkoxy- or lower alkanoyloxy)- lower alkyl-(diio, sulfinyl or sulfonyl), (amino-, lower alkylamino-, dilower alkylamino- or lower alkanoylamino)-lower alkyl-(thio, sulfinyl or sulfonyl), (hydroxy-, lower alkoxy- or lower alkanoyloxy)lower alkoxylower alkyl-(thio, sullinyl or sulfonyl), (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkoxylower alkyl-(thio, sulfinyl or sulfonyl), (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkylaminolower alkyl(thio, sulfinyl or sulfonyl), (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkylaminolower alkyl-(thio, sulfinyl or sulfonyl), carboxylower alkylthio, lower alkoxycarbonyllower alkylthio, aminocarbonyllower alkylthio, N-lower alkylaminocarbonyllower alkylthio, N,N-di-lower alkylaminocarbonyllower alkylthio, halogen, carboxyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylarrünocarbonyl, N-[(hydroxy-, lower alkoxy- or Lower alkanoyloxy)-lower alkyl]-aminocarbonyl, N-[(amino-, lower-alkylamino-, di-lower-alkylamino- or lower alkanoylamino)-lower alkyl]-aminocarbonyl, N-[(piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkyl]-aminocarbonyl, N-[(imidazolyl-, triazolyl-, pyride yl-, pyrimidinyl- or pyrrolyl)-lower alkyl]-aminocarbonyl, N-(hydroxysulfonyl-lower alkyl)-aminocarbonyl, N,N-di-lower alkylaminocarbonyl, cyano, amidino, formamidino and guanidino,

R₂ is hydrogen, lower alkyl or halogen,

R₃ represents phenyl which is unsubstituted or substituted by one, two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, C₁-C₃ alkylenedioxy, cyano and halogen,

with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R₁ represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl ,

and salts thereof, processes for preparing these compounds, pharmaceutical compositions containing these compounds and the use of these compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions.

In the context of the present invention, the general expressions used above and below have the following meanings:

The prefix "lower" stands for a radical with up to and including 7 carbon atoms, and in particular up to and including 4 carbon atoms.

Loweralkyl stands for example for n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl or methyl.

Halogen stands for chlorine, bromine or fluorine, for example, but can also be iodine.

Halogen-lower alkyl stands for example for halomethyl, for example chloromethyl or for example trifluoromethyl.

Lower alkanoyl stands for acetyl, propionyl or pivaloyl, for example, but can also stand for formyl.

Hydroxysulfonyl stands for the group -SO₃H. Aminocarbonyl stands for -CONH₂. Amidino stands for -C(=NH)-NH₂, formamidino stands for -NH-CH(=NH) and guanidino stands for -NH-C(=NH)-NH₂.

In substituents containing groups such as hydroxy-lower alkoxy, amino-lower alkoxy, hydroxy-lower alkylamino, amino-lower alkylamino, hydroxy-lower alkylthio or amino-lower alkylthio, the two heteroatoms are preferably separated by at least two C atoms, in other words: the lower alkyl radical is in each case preferably selected such that at least two C atoms lie between the two heteroatoms.

Azacycloalkyl is a cycloalkyl radical with 3-8, in particular 5-7 ring atoms, in which at least one of the ring atoms is a nitrogen atom. Azacycloalkyl can additionally contain further ring heteroatoms, for example N, O or S and is, for example, piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl.

Azaheteroaryl is an aromatic radical with 3-7, in particular 5-7 ring atoms, in which at least one of the ring atoms is a nitrogen atom. Azaheteroaryl can additionally contain other ring atoms, such as N, O or S. It can also be partially saturated. Azaheteroaryl is, for example, imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl.

Residues such as piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolyl, triazolyl and pyrrolyl can be bonded via a ring nitrogen atom or a ring carbon atom, residues such as pyridyl or pyrimidinyl are preferably bonded via a C atom.

As is known, the azacycloalkyl radicals are bonded via a ring nitrogen atom, with the preferred ones being called piperidino, piperazino, morpholino, pyrrolidino, etc.

Salts of the compounds of formula I are in particular pharmaceutically acceptable salts, primarily acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates) or salts with strong organic carboxylic acids, such as lower alkanecarboxylic acids or aliphatic dicarboxylic acids, which can be unsaturated or hydroxylated, for example acetates, oxalates, malonates, maleates, fumarates, tartrates or citrates.

If the compounds of formula I contain an acidic group, corresponding salts with bases are also possible, for example corresponding alkali metal or alkaline earth metal salts, such as sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts, such as zinc or copper salts, or salts with ammonia or organic amines, such as cyclic amines, such as mono-, di- or tri-lower alkylamines, such as hydroxy-lower alkylamines, for example mono-, di- or tri-hydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines, or polyhydroxy-lower alkylamines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine. Suitable mono-lower alkylamines are, for example, ethylamine and t-butylamine, suitable di-lower alkylamines, for example diethylamine and diisopropylamine and suitable tri-lower alkylamines are, for example, trimethylamine and triethylamine. Corresponding hydroxy-lower alkylamines are, for example, mono-, di- and triethanolamine, hydroxy-lower alkyl-lower alkylamine, for example N,N-dimethylamino- and N,N-diethylaminoethanol. Compounds of formula I with an acid group, for example carboxyl, and a basic group, for example amino, can also occur, for example in the form of internal salts, that is to say in zwitterionic form, or part of the molecule can occur as an internal salt and another part as a normal salt. Salts which are unsuitable for pharmaceutical uses are also included, since they can be used, for example, to isolate and purify the free compounds of formula I and their pharmaceutically acceptable salts.

The compounds of formula I have useful pharmacological properties. In particular, they inhibit the activity of the protein tyrosine kinase pp60c-src at concentrations between about 0.001 and about 10 µM [test description: K. Farley et al., Anal. Biochem. 203 (1992) 151-157, purified enzyme is used here as described in N. B. Lydon et al., Biochem. J. 287 (1992) 985-993].

It is known that both a specific alteration in the c-src gene, which leads to the elimination of c-src, and an inhibition of the activity of the protein tyrosine kinase pp60c-src affect the bone resorption capacity of osteoclasts [elimination of c-src by genetic manipulation: see for example P. Soriano et al., Cell 64 (1991) 693-702, inhibition of the activity of the protein tyrosine kinase pp60c-src: see for example B. F. Boyce et al., J. Clin. Invest. 90 (1992) 1622-1627, T. Yoneda et al., J. Clin. Invest. 91 (1993) 2791-2795].

Due to their inhibitory effect on the protein kinase pp60c-src, the compounds of formula I are capable of inhibiting the bone resorption capacity of osteoclasts. This can be demonstrated, for example, by the so-called bone disc test on cortical bone discs from cattle using rat osteoclasts in concentrations between about 0.001 and about 10 uM [The bone disc test is described, for example, in Biochem. Biophys. Res. Comm. 188 (1992) 1097-1103]. At the same time, the compounds of formula I inhibit the formation of characteristic holes in bone discs in vitro.

In vivo, the activity of the compounds of formula I can be demonstrated, for example, in the Hock model in the rat. In this test, the compounds of formula I, when administered orally once per day in concentrations between about 1 and about 100 mg/kg body weight, completely or partially inhibit the bone loss for 3-4 weeks induced in rats by ovariectomy [The "Hock model" is described, for example, in Meub. Bone Dis. 5 (1984) 177-181].

The compounds of formula I are therefore very suitable for the treatment of diseases that respond to the inhibition of the activity of the protein tyrosine kinase pp60c-src. Osteoporosis can be mentioned here in particular and also other diseases in the course of which bone resorption by osteoclasts plays a role, for example tumor-induced hypercalcemia, Paget's syndrome or the treatment of bone metastases, and also inflammatory processes in joints and bones and degenerative processes in cartilage tissue. In addition, the compounds of formula I are useful for the treatment of benign or malignant tumors that respond to the inhibition of the protein tyrosine kinase pp60c-src, for example breast cancer (mammary carcinoma) or colon cancer (colon carcinoma). They are also capable of inducing tumor regression and preventing tumor metastasis and the growth of micrometastases. The compounds of formula I are also useful for the treatment of cardiovascular disorders such as thrombosis.

The compounds of formula I also inhibit the activity of other non-receptor protein tyrosine kinases, for example (a) other members of the src family, for example lek and fyn, (b) Abl kinase and (c) ZAP70 kinase. In addition, the compounds of formula I also inhibit the activity of the receptor protein tyrosine kinases, for example (a) the EGF family, for example the EGF receptor, c-erbB2, c-erbB3 and cerbB4 and (b) the PDGF family, for example the PDGF receptor, CSF-1, Kit, VEGF and FGF. Due to these effects, the compounds of formula I can also be used for immunomodulation and for the treatment of disorders of the immune system, for example in inflammation or organ transplantation. They are also useful for the treatment of (hyper)proliferative disorders such as psoriasis, tumors, carcinomas and leukemias and for fibrosis and restenosis. The compounds of formula I can also be used for the treatment of disorders in the central or peripheral nervous system if signal transmission by at least one protein kinase is involved.

The invention primarily relates to the compounds of formula I, wherein

R₁ represents phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, halogen lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, Di-lower alkylaminone-lower alkyl, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkyl, (imidlazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkyl, hydroxy-lower aikyl-amino-lower alkyl, amino-lower akylamino-lower alkyl, (piperidinyl-, piperazinyl-, morph olinyl- or pyrrolidinyl)-lower alkylaminone-lower alkyl, (imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkylaminone-lower alkyl, mercaptone-lower alkyl, lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxy-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, amino-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxyl, lower alkoxy, C₁-C₃ Allcylendicxy, phenyl lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, lower alkanoyloxy lower alkoxy, amino lower alkoxy, lower alkylaminone lower alkoxy, di lower alkylaminone lower alkoxy, (piperidinyl- piperazinyl-, mozpholinyl- or pyrrolidinyl)-lower alkoxy, (imidazolyl-triazolyl-, Pyridyl, pyrimidinyl or pyrrolyl) lower alkoxy, hydroxy lower alkylaminone lower alkoxy, amino lower alkylaminone lower alkoxy, (piperidinyl, piperazinyl, morpholinyl or pyrrrolidinyl) lower alkylaminone lower alkoxy, (imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl) lower alkylamine on lower alkoxy, Hydroxysulfonyl lower alkoxy, amino, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolyl, mercapto, lower alkyl (thio, sulfinyl or sulfonyl), hydroxy lower alkyl (thio, sulfinyl or sulfonyl), amino lower alkyl (thio, s ulfinyl or sulfonyl), halogen, carboxyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N-(hydroxy-lower alkyl)-aminocarbonyl, N-(amino-lower alkyl)-aminocarbonyl, N-[(piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkyl]-aminocarbonyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl)-lower alkyl]-aminocarbonyl, N-(hydroxysulfonyl-lower alkyl)-aminocarbonyl, N,N-di-lower alkylaminocarbonyl and cyano, and

R₂ and R₃ are as defined above,

with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R₁ represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl ,

and pharmaceutically acceptable salts thereof.

The invention particularly relates to the compounds of formula I, wherein

R1; represents phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, hydroxy lower alkyl, halogen lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, di lower alkylamino lower alkyl, (pyrimidinyl, piperazinyl or morpholinyl) lower alkyl, (imidazolyl, triazolyl, pyridyl or pyrrolyl) lower alkyl, hydroxy lower alkylamino lower alkyl, amino lower alkylamino lower alkyl, (pyimidinyl, piperazinyl or morpholinyl) lower alkylamino lower alkyl, (imidazolyl, triazolyl, pyridyl or pyrrolyl) lower alkylamino lower alkyl, mercapto lower alkyl, lower alkyl (thio, suffinyl or sulfonyl) lower alkyl, hydroxy lower alkyl (thio, sulfinyl or sulfonyl)-lower alkyl, amino-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxyl, lower alkoxy, C₁-C₃ Alkylendioxy, Phenylrüederalkoxy, Hydroxyniederalkoxy, Aminoniederalkoxy, Niederalkylaminoniederalkoxy, Diniederalkylaminoniederalkoxy, (Pyrimidinyl-, Piperazinyl- oder Morpholinyl)-nederalkoxy, (Imidazolyl- Triazolyl-, Pyridyl- oder Pyrrolyl)-niederalkoxy, Hydroxyniederalkylaminoniederalkoxy, Aminoniederalkylaminoruederalkoxy, (Pyrimidinyl-, Piperazinyl-oder Morpholinyl)-niederalkylaminoniederalkoxy, (Imidazolyl-, Triazolyl-, Pyridyl- oder Pyrrolyl)-niederalkylaminoniederalkoxy, Hydroxysulfonylniederallcoxy, Amino, Pyrimidinyl, Piperazinyl, Morpholinyl, Imidazolyl, Triazolyl, Pyridyl, Pyrrolyl, Mercapto, Niederalkyl-(thio, sulfinyl or sulfonyl), hydroxy-lower alkyl (thio, sulfinyl or sulfonyl), amino-lower alkyl (thio, sulfinyl or sulfonyl), halogen, carboxyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N-(hydroxy-lower alkyl)-aminocarbonyl, N-(amin-lower alkyl)-aminocarbonyl, N-[(pyrimidinyl-, piperazinyl- or morpholinyl)-lower alkyl]-aminocarbonyl, N-[(imidazolyl-, triazolyl-, pyridyl- or pyrrolyl)-lower alkyl]-aminocarbonyl, N-(hydroxysulfonyl). deralkyl)-aminocarbonyl, N,N-di-lower alkylaminocarbonyl and cyano, and

R₂ is as defined above, and

R₃ and R₃' are PiLenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, phenyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, C₁-C₃ alkylenedioxy, cyano and halogen,

with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R₁ represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl,

and pharmaceutically acceptable salts thereof.

Subgroups of a group of compounds of formula I that should be highlighted in any case are:

(a) compounds of formula I in which R1 is phenyl which is unsubstituted or monosubstituted at position 3 or 4, (b) compounds of formula I in which R1 is phenyl which is monosubstituted at position 3, (c) compounds of formula I in which R1 is phenyl which is substituted at position 3 or 4 by I-imidazolyl-lower alkoxy, (d) compounds of formula I in which R3 is phenyl which is substituted at position 3 or 4 by hydroxyl and, if desired, additionally carries 1 or 2 further substituents selected from lower alkyl, hydroxyl, lower alkoxy and halogen, (e) compounds of formula I in which R3 is is phenyl which is monosubstituted at position 3 or 4 by hydroxyl, (f) compounds of formula I wherein R3 is phenyl which is (1) monosubstituted at position 3 by methoxy or chlorine, or (2) monosubstituted at position 3 or 4 by lower alkyl, hydroxy-lower alkyl, phenyl, hydroxyl, C2-C7 alkoxy, phenyl-lower alkoxy, cyano, fluorine or bromine, or (3) di- or trisubstituted by two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, cyano and halogen.

The invention particularly relates to the particular compounds and salts thereof described in the examples.

The invention further relates to the use of the compounds of formula I

wherein

R₁, R₂ and R₃ are as defined above,

or pharmaceutically acceptable salts thereof (for the manufacture of a medicament) for the treatment of conditions responsive to inhibition of the activity of protein tyrosine kinase pp60c-src.

The invention particularly relates to the use of the compounds of formula I in which R₁ is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl, R₂ is hydrogen and R₃ is phenyl, 4-methylphenyl, 4-methoxyphenyl or 4-chlorophenyl or pharmaceutically acceptable salts thereof.

The compounds of formula I can be prepared in a manner known per se by

(a) subjecting a compound of formula II

a ring closure reaction with synthesis of the pyrimidine ring, or

(b) subjecting a compound of formula III

a ring closure reaction with synthesis of the pyrimidine ring, or

(c) reacting a compound of formula IV

if desired after a temporary activation, with an aminating agent,

and, if desired, converting a compound of formula I into another compound of formula I and/or, if desired, a resulting salt into the free compound or into another salt and/or, if desired, a resulting free compound of formula I having salt-forming properties into a salt.

In the following more detailed description of the processes, the symbols R₁-R₃ are as defined under Formula I unless otherwise indicated.

Process (a): The reaction of process (a) corresponds to the cyclization of 2-amino-3-cyanopyrroles to 4-aminopyrrolo[2,3-d]pyrimidines, which is known per se (see, for example, H. Pichler et al., Liebigs Ann. Chem. 1986, 1485-1505). Possible cyclization reagents are, for example, (1) formamide or (2) 1. trialkylorthoformate / 2. ammonia. The cyclization of the compounds of formula II with formamide is preferably carried out at elevated temperature, for example 160°C, and advantageously with the addition of some DMF and formic acid. The reaction of the compounds of formula II with trialkylorthoformates to form the corresponding alkoxyformimidates, which are formed as intermediates, is normally carried out at not quite so high temperatures, for example 80-120°C. Typically, the cyclization of the latter with NH3 is then carried out again at higher temperatures, for example at 130ºC in an autoclave.

The compounds of formula II are preferably prepared by one of the known pyrrole syntheses. They are obtained, for example, by reacting a compound of formula IIa

with malononitrile, preferably in the presence of a base, for example sodium ethoxide/ethanol.

The compounds of formula IIa can be prepared for example by reacting a compound R₃-C(=O)-CH(-R₂)-Hal [Hal = halogen], that is to say for example phenacyl bromide or chloride with a compound H₂N-R₁, for example aniline, preferably in the presence of a base such as sodium carbonate/ethanol or triethylamine/toluene.

Method (b): The ring closure to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine is carried out, for example, in the presence of suitable bases, for example sodium ethoxide/ethanol, preferably at elevated temperature, such as 80ºC [see, for example, E. C. Taylor et al., J. Amer. Chem. Soc. 87 (1965) 1995-2003].

The amidine compounds of formula III can be prepared, for example, from the corresponding amino compounds of formula II according to known amidine syntheses, for example by reaction first with triethyl orthoformate, preferably at elevated temperature, and then with ammonia, preferably at room temperature.

Process (c): Various processes are known for converting 4-hydroxypyrrolo[2,3-d]pyrimidines to 4-aminopyrrolo[2,3-d]pyrimidines. The compounds of formula IV can thus be converted in the meantime, for example by reaction with a halogenating agent, for example PCl₅ or POCl₃, into the 4-halogen derivatives, which are then further reacted with ammonia. Another process consists of derivatizing the compounds of formula IV first with a sulfonyl halide, for example tosyl, mesyl or trifluoromethylsulfonyl chloride, and then reacting with ammonia.

The compounds of formula IV can be prepared, for example, from the corresponding compounds of formula II by ring closure, for example with formic acid, preferably at elevated temperature, such as 160ºC. A further process for the preparation of the compounds of formula IV consists of a first cyclization of a compound of formula IIa with malonic acid mononitrile monoalkyl ester to form the corresponding alkylpyrrole-3-carboxylate of formula IVa

(Alk = alkyl, e.g. ethyl). This is further cyclized, for example by reaction with formamide at 160ºC to form the 4-hydroxypyrrolo[2,3-d]pyrimidine of formula IV.

The compounds of formula I can be converted into other compounds of formula I.

Substituents in the aryl radical R₁ can, for example, be converted into one another in a manner known per se.

Halogen lower alkyl, for example chloromethyl, can be reacted, for example, with a nucleophilic substitution reaction, for example with substituted or unsubstituted lower alkanols, lower alkanethiols or lower alkylamines, to give substituted or unsubstituted lower alkoxy lower alkyl, lower alkylthio lower alkyl or lower alkylamino lower alkyl.

Hydroxy can, for example, be reacted with substituted or unsubstituted halo-lower alkanes to give substituted or unsubstituted lower alkoxy. Hydroxyl can also be reacted, for example first with a dihalo-lower alkane such as 1-bromo-2-chloroethane to give omega-halo-lower alkoxy, which can be reacted in an analogous manner as described above with substituted or unsubstituted lower alkanols, lower alkanethiols or lower alkylamines according to a nucleophilic substitution reaction to give substituted or unsubstituted lower alkoxy-lower alkoxy, lower alkylthio-lower alkoxy or lower alkylamino-lower alkoxy.

In an analogous manner to hydroxyl, mercapto can also be alkylated as in the previous section.

Lower alkylthio groups can be converted to either alkylsuffinyl or lower alkylsulfonyl groups by controlled oxidation.

Amino groups and hydroxyl groups can be acylated in a known manner to give, for example, lower alkanoylamino and lower alkanoyloxy groups.

Carboxylic acid residues can be converted into carboxylic acid derivatives, for example lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N,N-di-lower alkylaminocarbonyl, cyano or amidino according to known derivatization processes, for example esterification or amide formation. Conversely, carboxylic acid derivatives can also be converted into the free carboxylic acids, for example by hydrolysis.

The compounds of formula I in which R2 is hydrogen can be converted into the compounds of formula I in which R2 is halogen by reaction with a halogenating agent, for example an N-halosuccinimide.

If any intermediates contain interfering reactive groups, such as carboxyl, hydroxyl, mercapto or amino groups, these can be temporarily protected by easily removable protecting groups The choice of suitable protecting groups, their introduction and removal are known per se and are described, for example, in JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press, London, New York 1973.

Salts of the compounds of formula I can be prepared in a manner known per se. Acid addition salts of the compounds of formula I are thus obtained, for example by treatment with a suitable acid or a suitable ion exchange reagent and salts with bases are obtained by treatment with a suitable base or a suitable ion exchange reagent. Salts of the compounds of formula I can be converted into the free compounds in a conventional manner, acid addition salts, for example by treatment with a suitable basic agent or a suitable ion exchange reagent and salts with bases are converted, for example by treatment with a suitable acid or a suitable ion exchange reagent.

Salts of the compounds of formula I can be converted into other salts of the compounds of formula I in a manner known per se. Acid addition salts can, for example, be converted into other acid addition salts by treating a salt of an inorganic acid, such as a hydrochloride, with a suitable metal salt, such as sodium, barium or silver salt of an acid, for example silver acetate, in a suitable solvent, in which an inorganic salt is formed, for example silver chloride, which is insoluble and thus separates from the reaction mixture.

Depending on the process and the reaction conditions, the compounds of formula I with salt-forming properties can be obtained in free form or in the form of salts.

In view of the close relationship between the compounds of formula I in free form and in the form of their salts, hereinbefore and hereinafter the free compound of formula I or its salts are analogously and conveniently understood to mean also the corresponding salts or the free compound of formula I, where appropriate.

The compounds of formula I, including their salts of the salt-forming compounds, can also be obtained in the form of their hydrates and/or contain other solvents, for example solvents which were used for the crystallization of the compounds occurring in solid form.

The compounds of formula I and their salts may, depending on the starting compounds and processes, exist in the form of one of the possible isomers or as a mixture thereof. In this case, for example, pure diastereomers are available as pure enantiomers. Accordingly, mixtures of diastereomers may exist as mixtures of isomers. Isomer mixtures of the compounds of formula I in free form or in salt form, which can be obtained by this process or in other ways, can be separated into the components in a conventional manner, for example in a manner by fractional crystallization, distillation and/or chromatography based on the physicochemical differences of the constituents. Advantageously, the more active isomer is isolated.

The invention also relates to the embodiments of the process according to the invention according to which the starting material used is a compound which can be obtained as an intermediate in any stage of the process and the missing steps are carried out or a starting compound in the form of a derivative or salt is used or is particularly formed under the reaction conditions.

In the process according to the invention, the starting compounds and intermediates, in each case in free form or salt form, are preferably used which lead to the compounds of formula I or their salts which were described at the outset as being particularly useful. New starting materials and intermediates, in each case in free form or in salt form, for the preparation of the compounds of formula I or their salts, their use and processes for their preparation also form part of the invention, wherein the variable R is as defined for the compounds of formula I.

The invention also relates to the use of the compounds of formula I and their pharmaceutically acceptable salts for the treatment of allergic conditions and disorders, preferably in the form of pharmaceutically acceptable preparations, in particular in a method for the therapeutic treatment of the animal or human body, and to such a treatment method.

The invention also relates to pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient and to processes for their preparation. These pharmaceutical compositions are, for example, those for enteral, in particular oral and also rectal, administration, those for parenteral administration and those for local administration to warm-blooded animals, in particular humans, wherein the pharmacologically active ingredient is contained by itself or together with conventional pharmaceutical excipients. The pharmaceutical compositions contain (in percent by weight), for example, about 0.001% to 100%, preferably about 0.1% to 50% of the active ingredient.

Pharmaceutical compositions for enteral or parenteral administration are, for example, those in unit dosage forms such as sugar-coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. Pharmaceutical compositions for oral administration can therefore be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture and if desired or necessary processing the mixture or granules after the addition of suitable excipients to form tablets or sugar-coated tablet cores.

Suitable carriers are in particular fillers, such as types of sugar, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate and also binding agents, such as starch pastes, for example corn, wheat, rice or potato starch being used, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone and/or if desired disintegrants, such as the types of starch mentioned above and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are primarily flow regulators and lubricants, for example salicylic acid, talc, stearic acid and salts thereof, such as magnesium stearate or calcium stearate and/or polyethylene glycol. Sugar-coated tablet cores can be provided with suitable, if desired enteric, coatings using, inter alia, concentrated sugar solutions containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or sugar-coated tablets, for example for identification or to characterize the different dosages of the active ingredient.

Other orally administered pharmaceutical preparations are hard gelatin capsules and also soft-capped capsules made from gelatin and a plasticizer such as glycerin or sorbitol. Hard capsules can contain the active ingredient in the form of granules, for example mixed with fillers such as lactose, binding agents such as starches and/or lubricants such as talc or magnesium stearate and, if desired, stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid such as a fatty oil, paraffin oil or liquid polyethylene glycols, to which a stabilizer can be added.

Suitable pharmaceutical compositions that can be administered rectally are, for example, suppositories that contain a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. In addition, rectal gelatin capsules can also be used that contain a combination of the active ingredient with a base substance. Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral nutrition, aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, are primarily suitable and suppositories of the active ingredient, such as suitable oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil or synthetic solid acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran and, if desired, also stabilizers, are also used.

Pharmaceutical compositions for local administration are, for example, lotions, creams and ointments for the topical treatment of the skin, i.e. liquid or semi-solid oil-in-water or water-in-oil emulsions, fatty ointments which are anhydrous, pastes, i.e. creams and ointments containing secretion-absorbing powder components, gels which are aqueous, have little water or are anhydrous and consist of swellable, gel-forming materials, foams, i.e. liquid oil-in-water emulsions which are in aerosol form which are administered from pressurized containers, and tinctures which contain an aqueous-ethanolic base which in any case may contain other conventional pharmaceutical excipients such as preservatives. The pharmaceutical compositions for local administration are prepared in a conventional manner known per se by mixing the active ingredient with the pharmaceutical excipients, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. For the preparation of emulsions in which the active ingredient is dissolved in one of the liquid phases, as a rule the active ingredient is dissolved in this before emulsification, for the preparation of suspensions in which the active ingredient is suspended in the emulsion, the active ingredient is mixed with a part of the base after emulsification and then the rest of the formulation is added.

The dose of the active ingredient may depend on various factors, such as the effectiveness and duration of the effectiveness of the active ingredient, the severity of the disease to be treated and its symptoms, the method of administration, the type of warm-blooded animal, the sex, age, weight and/or individual condition of the warm-blooded animal. In normal cases, for example, a daily oral dose of about 1 mg to about 1000 mg, in particular about 5 to about 200 mg, is estimated for a warm-blooded animal weighing about 75 kg. This can be administered, for example, as a single dose or in several divided doses, such as 10 to 100 mg.

The following examples illustrate the invention described above. The temperatures are given in degrees Celsius, ether = diethyl ether, EA = ethyl acetate, THF = tetrahydrofuran, DMF = N,N-dimethylformamide. Hexane means an isomer mixture of various hexanes (Fluka), RE = rotary evaporator, RT = room temperature, HV = high vacuum, h = hour(s).

Reference Example 1: 5,7-Diphenyl-4-aminopyrrolo[2,3-d]pyrimidine

20 g of 1,4-diphenyl-2-amino-3-cyanopyrrole are heated under reflux for 2.5 h in 400 ml of ethyl formate and 2 ml of acetic anhydride. The mixture is then concentrated in a RE and the residue is crystallized from ether/petroleum ether. 1,4-diphenyl-2-(N-ethoxyformimidato)-3-cyanopyrrole is obtained with a melting point of 90-92°C.

18 g of 1,4-diphenyl-2-(N-ethoxyformimidato)-3-cyanopyrrole are dissolved in 150 mL of warm ethanol and the solution is treated at RT with 250 mL of ammonia in ethanol (8%) and left overnight. The formed solid is filtered and dried to give 1,4-diphenyl-2-(N-formamidino)-3-cyanopyrrole with a melting point of 195ºC. The mother liquor is concentrated to two thirds, cooled to 0ºC and filtered to give additional 1,4-diphenyl-2-(n-formaminidino)-3-cyanopyrrole with a melting point of 195ºC.

500 mL of ammonia in 8% ethanol and 14 g of 1,4-diphenyl-2-(N-formamidino)-3-cyanopyrrole are heated at 130ºC for 4 hours in an autoclave. After cooling to RT, the precipitated product is filtered off. The mother liquor is concentrated to two thirds and cooled to 0ºC and filtered to give additional product. The product is dissolved in hot ethanol/chloroform and the solution is treated with activated carbon and filtered. The chloroform is slowly stripped off in a RE to crystallize pure 5,7-diphenyl-4- aminopyrrolo[2,3-d]pyrimidine. After filtration and drying under HV, 5,7-diphenyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 200-201°C. 1H-NMR (CDCl3): δ (ppm) = 5.4 (br s, 2H), 7.3-7.6 (m, 9H), 7.8 (d, 2H), 8.35 (s, 1H).

(a) 1,4-Diphenyl-2-amino-3-cyanopyrrole: 3 g of sodium are dissolved in 300 ml of ethanol and then first 7.6 g of malononitrile and then 20 g of 2'-(phenylamino)acetophenone are added at RT and the mixture is heated to 80°C for 1.25 h. The mixture is then treated with hot water until it becomes cloudy and is then cooled, whereby the product crystallizes. After filtration and drying under HV, 1,4-diphenyl-2-amino-3-cyanohyrrole is obtained with a melting point of 135°C.

(b) 2'-Phenylaminoacetophenone: 40 g of phenacyl bromide and 20 ml of aniline are stirred at 70°C for 3 h in 500 ml of ethanol in the presence of 80 g of powdered Na₂CO₃. The mixture is cooled, treated with water and filtered. The crystals are dissolved in methylene chloride, then washed with water, dried over MgSO₄ and concentrated to two thirds. After addition of petroleum ether the product crystallizes and after filtration and drying under HV 2'-(phenylamino)acetophenone is obtained with a melting point of 95°C.

Example 2: 5,7-Diphenyl-6-methyl-4-aminopyrrolo[2,3-d]pyrimidine

0.8 g of 1,4-diphenyl-5-methyl-2-amino-3-cyanopyrrole are heated to 190°C in 1 ml of formamide under a nitrogen atmosphere for 2.5 h. After cooling to RT, the mixture is dissolved in a little methylene chloride and chromatographed on silica gel (methylene chloride / methanol 20:1). After crystallization from ether, 5,7-diphenyl-6-methyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 170-172°C. 1H-NMR (CDCl3): δ (ppm) = 2.2 (s, 3H), 5.1 (br s, 2H), 7.3-7.6 (m, 10H), 8.3 (s, 1H).

(a) 1,4-Diphenyl-5-methyl-2-amino-3-cyanopyrrole: 0.5 g of sodium is dissolved in 100 ml of ethanol and then first 1.6 g of malononitrile and then 5 g of 2'-(phenylamino)-propiophenone are added at RT and the mixture is refluxed for 20 h. The mixture is cooled and concentrated in a RE. The residue is then partitioned between water and methylene chloride and the aqueous phase is extracted once more with methylene chloride. The combined organic phases are dried over MgSO4 and concentrated. The product is dissolved in ether, filtered and crystallized by the addition of petroleum ether. After filtration and drying under HV, 1,4-diphenyl-5-methyl-2-amino-3-cyanopyrrole is obtained with a melting point of 150°C.

(b) 2'-Phenylamimopropiophenone: 15 ml of 2'-bromopropiophenone and 9.5 ml of aniline are stirred at 55°C for 20 h in 200 ml of toluene in the presence of 14 ml of triethylamine. The mixture is cooled, treated with water and extracted. The organic phase is dried over MgSO4 and concentrated. The product is dissolved in petroleum ether, filtered and crystallized by cooling to 0°C. After filtration and drying under HV, 2'-(phenylamino)propiophenone is obtained with a melting point of 97-99°C.

Example 3: 5-(2-chlorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

4 g of 4-(2-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated at 190°C with a spatula tip of dimethylaminopyridine for 3.5 h under a nitrogen atmosphere in 50 ml of formamide. After cooling to RT, the mixture is treated with water and extracted three times with ethyl acetate. The organic phases are washed with water, dried over MgSO4 and concentrated. After chromatography on silica gel (methylene chloride: methanol = 14:1) and crystallization from ethyl acetate/ether, 5-(2-chlorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 175-176°C. 1H NMR (CDCl3): δ (ppm) = 4.9 (br s, 2H), 7.3 (s, 1H), 7.35-7.45 (m, 3H), 7.45-7.6 (m, 4H), 7.75 (d, 2H), 8.4 (s, 1H).

(a) 4-(2-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole: 4.0 g of potassium t-butoxide are dissolved in 80 mL of ethanol and then first 3.0 g of malononitrile and then 9 g of 2'-phenylamino-2-chloroacetophenone are added at RT and the mixture is stirred at 65°C for 2 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is again extracted with methylene chloride. The combined organic phases are dried over MgSO4 and concentrated. The product is chromatographed on silica gel using methylene chloride and the fractions containing the product are concentrated to give 4-(2-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole as a red, viscous oil, which is then directly processed further.

(b) 2'-Phenylamino-2-chloroacetophenone: 8 g of 2'-bromo-2-chloroacetophenone and 2.6 g of aniline are stirred at 60°C for 2.5 h in 100 mL of ethanol in the presence of 8 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted again with methylene chloride. The combined organic phases are dried over MgSO₄ and concentrated. The oily product is used in the next step without further purification.

(c) 2'-Bromo-2-chloroacetophenone: 15.2 g of copper (II) bromide (CuBr2) are initially introduced into 45 mL of EA and heated to 60°C with stirring. 5.0 g of 2-chloroacetophenone in 45 mL of chloroform are then added dropwise over 0.5 h and the mixture is boiled under reflux for 2.5 h. After cooling to RT, the suspension is filtered and the mother liquor is concentrated in a RE. The oily product is used in the next step without further purification.

Example 4: 5-(3-chlorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

1 g of 4-(3-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole is heated with a spatula tip of dimethylaminopyridine in 10 ml of formamide at 180°C for 14 h under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and the crystals obtained are filtered off, washed with water and dried. After chromatography on silica gel (methylene chloride/methanol 15:1), the fractions containing the product are concentrated, slurried in ether and filtered. 5-(3-chlorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 173-175°C. 1H NMR (d6-DMSO): δ (ppm) = 6.3 (br s, 2H), 7.3-7.55 (m, 6H), 7.65 (s, 1H), 7.8 (s, 1H), 7.85 (d, 2H), 8.2 (s, 1H).

(a) 4-(3-Chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole: 0.24 g of sodium is dissolved in 40 mL of ethanol and then 0.76 g of malononitrile and then 2.37 g of 2'-phenylamino-3-chloroacetophenone are added at RT and the mixture is stirred for 1.5 h at 50°C. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered off to give 4- (3-chlorophenyl)-1-phenyl-2-amino-3-cyanopyrrole. Further product is again obtained from the mother liquor.

(b) 2'-Phenylamino-3-chloroacetophenone: 3.5 g of 2'-bromo-3-chloroacetophenone and 1.53 g of aniline are stirred at 50°C for 1.5 h in 40 mL of ethanol in the presence of 3.5 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The residue is slurried in ether/petroleum ether and the crystals are filtered off to give 2'-phenylamino-3-chloroacetophenone.

(c) 2'-Bromo-3-chloroacetophenone: Analogously to Example 3, starting from 3-chloroacetophenone, after boiling under reflux for 4 hours, the oily product 2'-bromo-3-chloroacetophenone is obtained, which is used without further purification in the next step.

Example 5: 5-(3-Methoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

1.27 g of 4-(3-methoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated at 180°C with a spatula tip of dimethylaminopyridine for 7 h in 14 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and the crystals obtained are filtered off, washed with water and dried. After chromatography on silica gel (ethyl acetate/hexane 4:1), the fractions containing the product are concentrated, slurried in ether and filtered. 5-(3-methoxyphenyl)-7-phenyl-4-aminopyrrolo[24-d]pyrimidine is obtained with a melting point of 159-160°C. 1H-NMR (d6-DMSO): δ (ppm) = 3.8 (s, 3H), 6.3 (br s, 2H), 6.9 (br d, 1H), 7.1 (m, 2H), 7.3-7.45 (m, 2H), 7.55 (t, 2H), 7.75 (s, 1H), 7.9 (d, 2H), 8.2 (s, 1H).

(a) 4-(3-Methoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole: 0.12 g of sodium is dissolved in 20 mL of ethanol and then first 0.32 g of malononitrile and then 1.06 g of 2'-phenylamino-3-methoxyacetophenone are added at RT and the mixture is stirred at 50°C for 2.5 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and EA and the aqueous phase is extracted twice with EA. The combined organic phases are dried over Na₂SO₄ and concentrated. The oily product 4-(3-methoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole is used in the next step without further purification.

(b) 2'-Phenylamino-3-methoxvacetophenone: 2 g of 3-methoxyphenacyl bromide and 0.89 g of aniline are stirred at 50°C for 1.5 h in 20 mL of ethanol in the presence of 2.0 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered off to give 2'-phenylamino-3-methoxyacetophenone. Additional product is obtained again analogously from the mother liquor.

Example 6: 5-(4-Fluorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

4.78 g of 4-(4-fluorophenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated with a spatula tip of dimethylaminopyridine for 3.5 h in 50 ml of formamide under a nitrogen atmosphere at 180°C. After cooling to RT, the mixture is treated with water and extracted three times with EA. The organic phases are washed with water, dried over Na₂SOa and concentrated. The residue is slurried in EA/ether and the crystals are filtered off. The crystals are suspended in hot ethanol and, after cooling to RT, filtered off. 5-(4-fluorophenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 202-203°C. 1H-NMR (d₆-DMSO): δ (ppm) = 6.3 (br s, 2H), 7.3-7.4 (m, 3H), 7.5-7.65 (m, 4H), 7.75 (s, 1H), 7.85 (d, 2H), 8.2 (s, 1H).

(a) 4-(4-Fluorophenyl)-1-phenyl-2-amino-3-cyanopyrrole: 0.57 g of sodium is dissolved in 80 mL of ethanol and then first 1.79 g of malononitrile and then 5.17 g of 2'-phenylamino-4-fluoroacetophenone are added at RT and the mixture is stirred for 2.5 h at 50°C. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered off to give 4-(4- Fluorophenyl)-1-phenyl-2-amino-3-cyanopyrrole is obtained. Further product is again obtained analogously from the mother liquor.

(b) 2'-Phenylamino-4-fluoroacetophenone: 5 g of 4-fluorophenacyl chloride and 3 g of aniline are stirred at 50°C for 1.75 h in 50 mL of ethanol in the presence of 6.7 g of powdered Na₂CO₃ and 0.87 g of NaI. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether and the crystals are filtered to give 2'-phenylamino-4-fluoroacetophenone. Additional product is obtained again analogously from the mother liquor after the addition of petroleum ether.

Example 7: 5-(2-methylphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

7.1 g of 4-(2-methylphenyl)-1-phenyl-2-amino-3-cyanopyrrole are heated at 160°C for 8 h in a mixture of 60 ml of formamide, 30 ml of formic acid and 14 ml of dimethylformamide. After cooling to RT, formic acid and DMF are stripped off in a RE and the residue is treated with water, neutralized and extracted three times with methylene chloride. The organic phases are washed with water, dried over Na₂SO₄ and concentrated. After chromatography on silica gel (EA/hexane 4:1), the fractions containing the product are concentrated, slurried in ether and filtered. 5-(2-methylphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 181-182°C. 1 H-NMR (d6 -DMSO): ? (ppm) = 2.25 (s, 3H), 6.3 (br s, 2H), 7.3-7.4 (m, 5H), 7.55 (m, 2H), 7.65 (s, 1H), 7.9 (d, 2H), 8.2 (s, 1H).

(a) 4-2-(methylphenyl)-1-phenyl-2-amino-3-cyanopyrrole: 0.83 g of sodium is dissolved in 80 mL of ethanol and then 2.61 g of malononitrile and then 7.4 g of 2'-phenylamino-2-methylacetophenone are added at RT and the mixture is stirred at 50°C for 4 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The oily product 4-(2-methylphenyl)-1-phenyl-2-amino-3-cyanopyrrole is used in the next step without further purification.

(b) 2'-Phenylamino-2-methylacetophenone: 8.0 g of 2-methylphenacyl bromide and 3.3 ml of aniline are stirred at 50°C Rk for 3 h in 80 ml of ethanol in the presence of 7.67 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The oily product 2'-phenylamino-2-methylacetophenone is used in the next step without further purification.

(c) 2'-Bromo-2-methylacetophenone: Analogously to Example 3, starting from 2-methylacetophenone, the oily product 2'-bromo-2-methylacetophenone is obtained, which is used in the next step without further purification. [35.0 g of copper (II) bromide (CuBr₂) are initially introduced into 90 ml of EA and the mixture is heated to 60°C with stirring. 10.0 g of 2-methylacetophenone in 90 ml of chloroform are then added dropwise over 0.75 h. and the mixture is boiled under reflux for 1.5 h. After cooling to RT, the suspension is filtered and the mother liquor is concentrated in a RE. The oily product is used in the next step without further purification].

Example 8: 5,7-Bis(4-fluorophenyl)-4-aminopyrrolo[2,3-d]pyrimidine

3.6 g of 1,4-bis(4-fluorophenyl)-2-amino-3-cyanopyrrole and 0.6 ml of acetic anhydride are boiled under reflux in 50 ml of triethyl orthoformate for 2.5 h. After cooling to RT, the mixture is treated with hexane and cooled to 0°C and the crystals are filtered off and washed with hexane. 1,4-bis(4-fluorophenyl)-2-(N-ethoxyformimidato)-3-cyanopyrrole is obtained.

150 ml of ammonia in ethanol (about 8%) and 3.65 g of 1,4-bis(4-fluorophenyl)-2-(N-ethoxyformimidato)-3- cyanopyrrole are heated at 130°C for 5 h in an autoclave. After cooling to RT, the mixture is concentrated to 3/4 and the residue is treated with ether. The precipitated product is filtered off and washed with ether. After filtration and drying and HV, 5,7-bis(4-fluorophenyl)-4- aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 253-254°C. ¹H-NMR (4-DMSO): δ; (ppm) = 6.3 (br s, 2H), 7.3-7.4 (m, 4H), 7.5-7.65 (m, 2H), 7.7 (s, 1H), 7.9 (m, 2H), 8.2 (s, 1H).

(a) 1,4-bis(4-fluorophenyl)-2-amino-3-cyanopyrrole: 0.56 g of sodium is dissolved in 90 mL of ethanol and then 1.75 g of malononitrile and then 5.48 g of 2'-(4-fluorophenylamino)-4-fluoroacetophenone are added at RT and the mixture is stirred at 50°C for 1.5 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered off to give 1,4- bis(4-fluorophenyl)-2-amino-3-cyanopyrrole. Further product is again obtained analogously from the mother liquor.

(b) 2'-(4-Fluorophenylamino)-4-fluoroacetophenone: 5 g of 4-fluorophenacyl chloride and 3.54 g of 4-fluoroaniline are stirred at 50°C for 1.5 h in 50 mL of ethanol in the presence of 6.7 g of powdered Na₂CO₃ and 0.87 g of Na₁. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered to give 2'-(4-fluorophenylamino)-4-fluoroacetophenone. Further product is again obtained analogously from the mother liquor after the addition of petroleum ether.

Example 9: 5-Phenyl-7-(3-ethoxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine

4.75 g of 4-phenyl-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole and 0.8 ml of acetic anhydride are boiled under reflux in 60 ml of triethyl orthoformate for 1.5 h. After cooling to RT, the mixture is concentrated in a RE. After chromatography of the oil on silica gel (methylene chloride / hexane 3:2), the fractions containing the product are concentrated. 4-phenyl = 1-(3-ethoxyphenyl)-2-(N-ethoxyformimidato)-3-cyanopyrrole is obtained in crystalline form.

160 ml of ammonia in ethanol (about 8%) and 4.28 g of 4-phenyl-1-(3-ethoxyphenyl)-2-(N-ethoxyformimidato)-3-cyanopyrrole are heated at 130°C for 6.5 h in an autoclave. After cooling to RT, the mixture is concentrated. After chromatography of the oil on silica gel (methylene chloride/methanol 95:5), the fractions containing the product are concentrated. The residue is slurried with ether and the crystals are filtered off. After filtration and drying under HV, 5-phenyl-7-(3-ethoxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 138-139°C. 1H-NMR (d6-DMSO): δ (ppm) = 1.35 (t, 3H), 4.1 (q, 2H), 6.2 (br s, 2H), 6.9 (br d, 1H), 7.35-7.6 (m, 9H), 7.75 (s, 1H), 8.2 (s, 1H).

(a) 4-Phenyl-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole: 0.4 g of sodium is dissolved in 70 mL of ethanol and then 1.24 g of malononitrile and then 4.0 g of 2'-(3-ethoxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50°C for 2 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated to give 4-phenyl-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole. The oily product is used in the next step without further purification.

(b) 2'-(3-Ethoxyphenylamino)acetophenone: 5 g of phenacyl bromide and 3.78 g of m-phenetidine are stirred at 50°C for 2.5 h in 50 mL of ethanol in the presence of 5.85 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether and the crystals are filtered to give 2'-(3- Ethoxyphenylamino)acetophenone. Additional product is obtained again analogously from the mother liquor after the addition of petroleum ether.

Example 10: 5-(3,5-Dimethoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine

1.81 g of 4-(3,5-dimethoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole and 0.3 ml of acetic anhydride are boiled under reflux in 25 ml of triethyl orthoformate for 2 h. After cooling to RT, the mixture is concentrated in a RE. 4-(3,5-dimethoxyphenyl)-1-phenyl-2-(N-ethoxyformimidato)-3-cyanopyrrole is obtained as a brown oil.

120 ml of ammonia in ethanol (about 8%) and 4.28 g of 4-(3,5-dimethoxyphenyl)-1-phenyl-2-(nethoxyformimidaio)-3-cyanopyrrole are heated at 130ºC for 3.5 h in an autoclave. After cooling to RT, the mixture is concentrated. The residue is treated with ether and the precipitated product is filtered off. The crystals are dissolved in hot ethanol/methylene chloride and the solution is treated with activated carbon, filtered and concentrated to 2/3 in a RE. After cooling to 0ºC, the crystals formed are filtered off. After drying under HV, 5-(3,5-dimethoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3- d]pyrimidine with a melting point of 211-212ºC is obtained. 1 H-NMR (d6 -DMSO): ? (ppm) = 3.8 (s, 6H), 6.3 (br s, 2H), 6.5 (br s, 1H), 6.7 (br s, 2H), 7.35 (m, 1H), 7.55 (m, 2H), 7.75 (s, 1H), 7.9 (d, 2H), 8.2 (s, 1H).

(a) 4-(3,5-Dimethoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole: 0.14 g of sodium is dissolved in 25 mL of ethanol and then first 0.45 g of malononitrile and then 1.54 g of 2'-phenylamino-3,5-dimethoxyacetophenone are added at RT and the mixture is stirred at 50°C for 1.5 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The oily product 4-(3,5-dimethoxyphenyl)-1-phenyl-2-amino-3-cyanopyrrole is used in the next step without further purification.

(b) 2'-(Phenylamino)-3,5-dimethoxyacetophenone: 8.0 g of 2'-bromo-3,5-dimethoxyacetophenone and 1.54 ml of aniline are stirred at 50°C for 1.5 h in 40 ml of ethanol in the presence of 3.59 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is taken up in a little ether and left to stand for three days at 0°C. The crystals are filtered off, washed with ether and dried under HV. 2'-Phenylamino-3,5-dimethoxyacetophenone is obtained.

(c) 2'-Bromo-3,5-dimethoxvacetophenone: Similar to Example 3, starting from 3,5-dimethoxyacetophenone, the oily product 2'-bromo-3,5-dimethoxyacetophenone is obtained, which is used in the next step without further purification.

Example 11: 5-Phenyl-7-(3-benzyloxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine

13.76 g of 4-phenyl-1-(3-benzyloxyphenyl)-2-amino-3-cyanopyrrole and 2.3 ml of acetic anhydride are boiled under reflux in 170 ml of triethyl orthoformate for 1.5 h. After cooling to RT, the mixture is concentrated in a RE. After chromatography of the oil on silica gel (methylene chloride / hexane 3:2), the fractions containing the product are concentrated. 4-phenyl-1-(3-benzyloxyphenyl)-2-(nethoxyformimidaro)-3-cyanopyrrole is obtained in crystalline form.

350 ml of ammonia in ethanol (about 8%) and 4.28 g of 4-phenyl-1-(3-ethoxyphenyl)-2-(N-ethoxyformimidato)-3-cyanopyrrole are heated at 130°C for 5 h in an autoclave. After cooling to RT, the mixture is concentrated. After chromatography of the oil on silica gel (methylene chloride / methanol 95:5), the fractions containing the product are concentrated. The residue is slurried with ether and the crystals are filtered off. After filtration and drying under HV, 5-phenyl-7-(3- ethoxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 141-142°C. 4-Phenyl-1-(3- ethoxyphenyl)-2-(n-formamidino)-3-cyanopyrrole is obtained as a by-product, which can be crystallized similarly to 5-phenyl-7-(3- ethoxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine at 160 °C in formamide, formic acid and DMF analogously to Example 7. 1H-NMR (d6-DMSO): δ (ppm) = 5.2 (s, 2H), 6.2 (br s, 2H), 7.0 (br d, 1H), 7.3-7.65 (m, 13H), 7.75 (s, 1H), 8.2 (s, 1H).

(a) 4-Phenyl-1-(3-benzyloxyphenyl)-2-amino-3-cyanopyrrole: 0.95 g of sodium is dissolved in 200 mL of ethanol and then 2.98 g of malononitrile and then 11.96 g of 2'-(3-benzyloxyphenylamino)acetophenone are added at RT and the mixture is stirred at 50°C for 2 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated to give 4-phenyl-1-(3-benzyloxyphenyl)-2-amino-3-cyanopyrrole. The oily product is used in the next step without further purification.

(b) 2'-(3-Benzyloxyphenylamino)acetophenone: 10 g of phenacyl bromide and 11 g of 3-benzyloxyaniline are stirred at 60°C for 2 h in 100 mL of ethanol in the presence of 11.7 g of powdered Na2CO3. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na2SO4 and concentrated. The residue is slurried with ether and the crystals are filtered to give 2'-(3-benzyloxyphenylamino)acetophenone.

Example 12: 5-Phenyl-7-(3-hydroxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine

2.61 g of 5-phenyl-7-(3-benzyloxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine (Ex. 11) and 1.0 g of 10% palladium on carbon are stirred in 100 mL of THF at 40 °C for 30 h until the theoretically required amount of hydrogen is consumed. After cooling to RT, the mixture is filtered and the filtrate is concentrated in a RE. The residue is slurried with ether and the crystals are filtered off. Recrystallization from methylene chloride/ethanol and from chloroform does not give pure product. After chromatography on silica gel (methylene chloride/methanol with NH3 (4 N) 92:8), the fractions containing the product are concentrated. The residue is dissolved in hot chloroform, the solution is cooled to 0°C and the crystals are filtered off. After filtration and drying under HV, pure 5-phenyl-7-(3-hydroxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 227-228°C. 1H-NMR (d6-DMSO): 8 (ppm) = 6.2 (br s, 2H), 6.8 (br d, 1H), 7.2-7.4 (m, 4H), 7.5-7.6 (m, 4H), 7.7 (s, 1H), 8.2 (s, 1H), 9.8 (s, 1H).

Example 13: 5-(3,4-Methylenedioxyphenyl)-7-(3-ethoxyphenyl)-4-aminopyrrolo[2, 3-d]pyrimidine

0.8 g of 4-(3,4-methylenedioxyphenyl)-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole are heated at 160°C for 6 h in a mixture of 8 ml of formamide, 4 ml of formic acid and 1.5 ml of DMF. After cooling to room temperature, the mixture is treated with water and the crystals obtained are filtered off, washed with water and dried. After chromatography on silica gel (EA/hexane 3:4), the fractions containing the product are concentrated, slurried in ether and filtered. After repeated chromatography on silica gel (methylene chloride/methanol with NH₃ (4 N) 97:3), the fractions containing the product are concentrated. The residue is slurried with ether/EA and the crystals are filtered off. 5-(3,4- methylenedioxyphenyl)-7-(3-ethoxyphenyl)4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 153-155°C. 1H-NMR (d6-DMSO): δ (ppm) = 1.35 (t, 3H), 4.1 (q, 2H), 6.1 (s, 2H), 6.25 (br s, 2H), 6.9 (br d, 1H), 7.0 (m, 2H), 7.1 (s, 1H), 7.4-7.5 (m, 3H), 7.7 (s, 1H), 8.2 (s, 1H).

(a) 4-(3,4-Methylendioxylene)-1-(3-ethoxyphenyl)-2-amino-3-cyanoyrrole: 0.19 g of sodium is dissolved in 40 mL of ethanol and then first 0.6 g of malononitrile and then 2.28 g of 2'-(3-ethoxyphenylamino)-3,4- methylenedioxyacetophenone are added at RT and the mixture is stirred at 50°C for 6 h. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether and the crystals are filtered off to give 4-(3,4-methylenedioxyphenyl)-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole. The oily mother liquor also mainly contains 4-(3,4-methylenedioxyphenyl)-1-(3-ethoxyphenyl)-2-amino-3-cyanopyrrole and can also be used in the next step.

(b) 2'-(3-Ethoxyphenylamino)-3,4-methylenedioxacetophenone: 2.4 g of 2'-bromo-3,4-methylenedioxyacetophenone and 1.49 g of m-phenetidine are stirred at 50°C for 5 h in 30 mL of ethanol in the presence of 2.3 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and methylene chloride and the aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether/petroleum ether and the crystals are filtered to give 2'-(3-ethoxyphenylamino)-3,4-methylenedioxyacetophenone.

(c) 2'-Bromo-3,4-methylenedioxyacetophenone: In an analogous manner to that described in Example 3, 2'-bromo-3,4-methylenedioxyacetophenone is obtained in crystalline form starting from 3,4-methylenedioxyacetophenone, which is used in the next step without further purification.

Example 14: Ethyl 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoate

0.5 g of ethyl 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate are heated to 190°C for 6 h in 1 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and the crystals are filtered off. The mixture is dissolved in a little methylene chloride, dried and concentrated. After chromatography on silica gel (methylene chloride/acetone 5:1), the fractions containing the product are concentrated. Ethyl 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoate is obtained with a melting point of 176-177°C. 1H-NMR (d6-DMSO): δ (ppm) = 1.4 (t, 3H), 4.4 (q, 2H), 5.2 (br s, 2H), 7.3 (s, 1H), 7.4-7.65 (m, 6H), (CDCl3 ) 8.05 (m, 2H), 8.3 (d, 1H), 8.4 (s, 1H).

(a) Ethyl 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate: 0.6 g of piperidine, 0.55 g of malononitrile and a catalytic amount of dimethylaminopyridine are boiled under reflux for 15 h in 50 ml of ethanol together with 2 g of 2'-(3- ethoxycarbonylphenylamino)acetophenone. The mixture is then cooled and concentrated in a RE. After chromatography on silica gel (methylene chloride), the fractions containing the product are concentrated. The product is dissolved in ether and crystallized by the addition of petroleum ether. After filtration, ethyl 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate is obtained with a melting point of 129-130ºC.

(b) 2'-(3-Ethoxycarbonylphenylamino)acetophenone: 4 g of phenacyl bromide and 5.2 g ethyl 3-aminobenzoate methanesulfonate are treated with 5.7 ml of triethylamine at RT with stirring in 50 ml of toluene and stirred at RT for 2 h. The mixture is treated with water and washed twice. The organic phase is dried over MgSO4 and the product is crystallized by the addition of petroleum ether and by cooling to 0°C. After filtration and drying under HV, 2'-(3-Ethoxycarbonylphenylamino)acetophenone is obtained with a melting point of 116-118°C.

Example 15: 3-(5-Phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid

0.8 g of sodium 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate are heated to 200°C for 6 h in 1 ml of formamide under a nitrogen atmosphere. After cooling to RT, the mixture is treated with water and acidified with glacial acetic acid. The crystals are filtered off and the product is recrystallized from hot glacial acetic acid. After filtration and drying under HV, pure 3-(5-phenyl-4-aminopyrrolo[2,3- d]pyrimidin-7-yl)'benzoic acid is obtained with a melting point > 300°C. 1H-NMR (d₆-DMSO): δ (ppm) = 6.2 (br s, 2H), 7.4 (m, 1H), 7.45-7.6 (m, 4H), 7.65 (t, 1H), 7.8 (s, 1H), 7.9 (d, 1H), 8.1 (d, 1H), 8.25 (s, 1H), 8.5 (s, 1H).

(a) Sodium 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate: 0.2 g of sodium is dissolved in 30 ml of ethanol and then first 0.55 g of malononitrile and then 2.0 g of 2'-(3-ethoxycarbonylphenylamino)acetophenone (see Example 14) are added at RT and the mixture is boiled at reflux for 2 h. The mixture is then cooled and the crystals are filtered off to give sodium 3-(4-phenyl-2-amino-3-cyanopyrrol-1-yl)benzoate with a melting point of > 300ºC.

Example 16: N-[2-(1-Piperazinyl)ethyl]-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide hydrochloride

1.5 g of 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid (Example 15) is dissolved in 40 mL of warm DMF and the solution is cooled to 0°C. The mixture is treated with 0.82 g of carbonyldiimidazole and stirred at 0°C for 2 h. 0.6 g of 1-(2-aminoethyl)piperazine is then added dropwise and the mixture is allowed to warm to RT and is stirred for 2 h. The mixture is then concentrated in a RE. The residue is treated with water and methylene chloride and an oil insoluble in both phases is filtered off. This oil is dissolved in dilute hydrochloric acid (0.1 N) and the aqueous phase is washed with methylene chloride, basified with 1 N NaOH and extracted with methylene chloride. The organic phase is dried over MgSO4 and concentrated. The residue is taken up in a little ethanol and adjusted to about pH 3 with ethanolic HCl. The crystals formed are filtered off and dried under HV at 100°C. The hydrochloride of N-[2-(1-piperazinyl)ethyl]-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide is obtained with a melting point of about 220°C.

Example 17: N-(2-Hydroxyethyl)-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide

1.0 g of 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid (Example 15) is dissolved in 25 mL of warm DMF and the solution is cooled to 0ºC. The mixture is treated with 0.54 g of carbonyldiiniidazole and stirred at RT for 2 h. 0.19 g of ethanolamine is then added dropwise and the mixture is allowed to warm to RT and stir for 3 h. The mixture is then concentrated in a RE. The residue is dissolved in methylene chloride and the solution is crystallized overnight at 0ºC. After filtration, the residue is dissolved in methylene chloride and chromatographed on silica gel (methylene chloride/methanol 15:1). The fractions containing the product are concentrated and the residue is taken up in a little methylene chloride and crystallized overnight at 0ºC. The crystals formed are filtered off and dried under HV. N-(2-hydroxyethyl)-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide is obtained with a melting point of 194-198ºC.

Analogously to the above examples, the following compounds are prepared from the corresponding substituted or unsubstituted haloacetophenones, in particular bromoacetophenone, and the appropriate unsubstituted or substituted anilines:

Example 18: 5-Phenyl-7-(3-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 163-168ºC

Example 19: 5-Phenyl-7-(3-chlorophenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 188-189ºC

Reference Example 20: 5-(4-Methoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 187-188°C

Example 21: 5-(3,4-Dimethoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 207-209ºC

Example 22: 5-Phenyl-7-(3,4-methylenedioxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 170-172ºC

Example 23: 5-Phenyl-7-(3,4-dimethoxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 147-149ºC

Example 24: 5-Phenyl-7-(2-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 174-175ºC

Example 25: 5-(3-Methoxyphenyl)-7-(3-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 151-152°C

Example 26: 5-(3-Methoxyphenyl)-7-(3,4-methylenedioxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, mp 188- 190ºC

Example 27: 5-Phcnyl-7-[4-(2-hydroxyethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 169-171°C

Example 28: 5-(3,4-Dimethoxyphenyl)-7-(3-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, mp 225°C

Example 29: 5-(4-Benzyloxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 180-181ºC

Starting from the compound of Example 29, namely 5-(4-benzyloxyphenyl)-7-phenyl-4- aminopyrrolo[2,3-d]pyrimidine, the following compound can be obtained by catalytic hydrogenation analogously to Example 12:

Example 30: 5-(4-Hydroxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 270-272ºC

Starting from the compound of Example 1, namely 5,7-diphenyl-4-aminopyrrolo[2,3-d]pyrimidine, the following compounds are obtained in an analogous manner by halogenation, for example using the corresponding N-halosuccinimide:

Example 31: 5,7-Diphenyl-6-chloro-4-aminopyrrolo[2,3-d]pyrimidine, mp 168ºC

Example 32: 5,7-Diphenyl-6-bromo-4-aminopyrrolo[2,3-d]pyrimidine, mp 167-169ºC

Starting from the compound of Example 18, namely 5-phenyl-7-(3-hydroxymethylphenyl)-4- aminopyrrolo[2,3-d]pyrimidine, the following compound is obtained in a known manner by treatment with chlorenamine (= 1-chloro-N,N-2-trimethylpropenylamine, see for example L. Ghosez, Adv. Org. Chem. Volume 9, Part 1, page 421):

Example 33: 5-Phenyl-7-(3-chloromethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, mp 150ºC

Starting from the compound of Example 33, the following compounds are obtained, for example by heating with a suitable amine with or without solvent or by reaction with an amine which has been deprotonated by sodium hydride or another strong base in an inert solvent:

Example 34: 5-Phenyl-7-[3-(1-imidazolylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 127-129ºC Example 35: 5-Phenyl-7-[3-(2-hydroxyethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine hydrochloride, mp 265ºC

Analogously to Example 17, starting from 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid (see Example 15) and the appropriate amine, the following compounds are obtained:

Example 36: N-(3-Hydroxypropyl)-3-(5-phenyl)-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide, mp 202-204°C

Example 37: N-(2-(4-Imidazolyl)ethyl)-3-(5-phenyl)-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide, mp 198- 200ºC

Analogous to the above examples, the following compounds can also be prepared using the described processes or using other conventional chemical processes:

Example 38: 5-(4-Hydroxyphenyl)-7-[3-(2-hydroxyethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 165ºC (decomposition)

Example 39: 5-(3-Methoxyphenyl)-7-[3-(2-hydroxyethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 40: 5-Phenyl-7-[3-(3-hydroxypropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 41: 5-Phenyl-7-[3-(4-hydroxybutyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 42: 5-Phenyl-7-[3-(2-aminoethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 43: 5-phenyl-7-[3-(3-aminopropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 44: 5-Phenyl-7-[3-(1-piperazinylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 45: 5-Phenyl-7-[3-(2-(1-piperazinyl)ethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 46: 5-Phenyl-7-[3-(2-(4-piperidinyl)ethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 47: 5-Phenyl-7-[3-(2-(4-imidazolyl)ethyl)aminomethylphenyl]4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 48: 5-Phenyl-7-[3-(2-pyridylmethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride, m.p. of the hydrochloride 220ºC

Example 49: 5-Phenyl-7-(4-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, mp 207-209ºC

Example 50: 5-Phenyl-7-(4-chloromethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine

Example 51: 5-Phenyl-7-[4-(2-hydroxyethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 120- 122ºC, or a salt thereof, for example the hydrochloride

Example 52: 5-Phenyl-7-[4-(3-hydroxypropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 53: 5-Phenyl-7-[4-(2-aminoethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 54: 5-Phenyl-7-[4-(3-aminopropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 55: 5-Phenyl-7-[4-(2-(1-piperazinyl)ethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 56: 5-Phenyl-7-[4-(2-(4-imidazolyl)ethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 57: 5-Phenyl-7-[3-(2-hydroxyethylthiomethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 58: 5-Phenyl-7-[4-(2-hydroxyethylthiomethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 59: 5-Phenyl-7-[3-(2-hydroxyethylsulfinylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 60: 5-Phenyl-7-[4-(2-hydroxyethylsulfinylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 61: 5-Phenyl-7-[3-(2-hydroxyethylsulfonylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 62: 5-Phenyl-7-[4-(2-hydroxyethylsulfonylmethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 63: 5-Phenyl-7-(2-chloromethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine

Example 64: 5-Phenyl-7-[2-(2-hydroxyethyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 170ºC, or a salt thereof, for example the hydrochloride

Example 65: 5-Phenyl-7-[2-(3-hydroxypropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine, or a salt thereof, for example the hydrochloride

Example 66: 5-Pihenyl-7-[2-(3-aminopropyl)aminomethylphenyl]-4-aminopyrrolo[2,3-d]pyrimidine, or a salt thereof, for example the hydrochloride

Example 67: 5-Phenyl-7-[2-(2-hydroxyethylthiomethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 68: 5-Phenyl-7-[3-cyanophenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 69: 5-Phenyl-7-[3-(1-imidazolyl)phenyl]-4-aminopyrrolo [2,3-d]pyrimidine

Example 70: 5-Phenyl-7-[4-cyanophenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 71: 5-Phenyl-7-[4-ethoxyphenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 72: 5-Phenyl-7-[4-benzyloxyphenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 73: 5-Phenyl-7-[4-hydroxyphenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 74: 5-Phenyl-7-[2-hydroxyphenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 75: 5-Phenyl-7-[4-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 76: 5-Phenyl-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 119-126ºC

Example 77: 5-Phenyl-7-[2-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 78: 5-(4-Hydroxyphenyl)-7-[4-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 221-222°C

Example 79: 5-(4-Hydroxyphenyl)-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, (amorphous foam). The compound is prepared analogously to Examples 1, 29, 30 and 155. The starting material used is 3-(2-hydroxyethoxy)aniline. This is prepared by reacting 3-fluoronitrobenzene with the monosodium salt of ethylene glycol and then converting the nitro group to the amino group.

Example 80: 5-(3-Methoxyphenyl)-7-[4-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine,

Example 81: 5-(3-Methoxyphenyl)-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 163-165°C

Example 82: 5-(4-Methoxyphenyl)-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine,

Example 83: 5-(4-Fluorophenyl)-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 84: 5-(3-Chlorophenyl)-7-[3-(2-hydroxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 85: 5-Phenyl-7-[3-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 86: 5-(4-Hydroxyphenyl)-7-[3-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 87: 5-(3-Methoxyphenyl)-7-[3-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 88: 5-Phenyl-7-[4-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 89: 5-(4-Hydroxyphenyl)-7-[4-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 90: 5-(3-Methoxyphenyl)-7-[4-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 91: 5-Phenyl-7-[2-(3-hydroxypropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 92: 5-Phenyl-7-[4-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 93: 5-Phenyl-7-[3-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 94: S-Phenyl-7-[2-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 95: 5-(4-Hydroxyphenyl)-7-[4-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d] pyrimidine

Example 96: 5-(4-Hydroxyphenyl)-7-[3-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 97: 5-(3-Methoxyphenyl)-7-[4-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 98: 5-(3-Methoxyphenyl)-7-[3-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 99: 5-(4-Methoxyphenyl)-7-[3-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 100: 5-Phenyl-7-[3-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 101: 5-(4-Hydroxyphenyl)-7-[3-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 102: 5-(3-Methoxyphenyl)-7-[3-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 103: 5-Phenyl-7-[4-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 104: 5-(4-Hydroxyphenyl)-7-[4-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 105: 5-(3-Methoxyphenyl)-7-[4-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 106: 5-Phenyl-7-[2-(3-aminopropoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 107: 5-Phenyl-7-[3-(2-(1-piperazinyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 108: 5-Phenyl-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 166-168°C or a salt thereof, for example the hydrochloride. The free compound is prepared from 5-phenyl-7-[3-(2- chloroethoxy)phemyl]-4-aminopyrrolo[2,3-d]pyrimidine and imidazolyl analogously to Example 155. 5-Phenyl-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3d]pyrimidine is obtained according to the usual synthesis procedure starting from phenacyl bromide and 3-(2-chloroethoxy)aniline [see Example 155 a].

Example 109: 5-Phenyl-7-[3-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 188 - 189 °C or a salt thereof, for example the hydrochloride. The free compound is obtained by the reaction of 5-phenyl-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (see Example 108) and 2-aminoethanol.

Example 110: 5-Phenyl-7-[3-(2-(2-aminoethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 111: 5-Phenyl-7-[3-(2-(2-(4-imidazolyl)ethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a Salt thereof, for example the hydrochloride

Example 112: 5-Phenyl-7-[4-(2-(1-piperazinyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 113: 5-Phenyl-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 114: 5-Phenyl-7-[4-(2-(2-(hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine or a salt thereof, for example the hydrochloride

Example 115: 5-Phenyl-7-[4-(2-hydroxyethylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 116: 5-Phenyl-7-[3-(2-hydroxyethyltrifluoro)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 147-150ºC

Example 117: 5-Phenyl-7-[4-(3-hydroxypropylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 118: 5-Phenyl-7-[3-(3-hydroxypropylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 119: 5-Phenyl-7-[4-(2-aminoethylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 120: 5-Phenyl-7-[3-(2-aminoethylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 121: 5-Phenyl-7-[4-(3-aminopropylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 122: 5-Phenyl-7-[3-(3-aminopropylthio)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 123: 5-Phenyl-7-[4-(2-hydroxyethylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 124: 5-Phenyl-7-[3-(2-hydroxyethylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 177-180°C

Example 125: 5-Phenyl-7-[4-(3-hydroxypropylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 126: 5-Phenyi-7-[3-(3-hydroxypropylsulfinyl)phenyl]-4-aminopyrroio[2,3-d]pyrimidine

Example 127: 5-Phenyl-7-[4-(2-aminoethylsulfinyl)phenyl]4-aminopyrrolo[2,3-d]pyrimidine

Example 128: 5-Phenyl-7-[3-(2-aminoethylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 129: 5-Phenyl-7-[4-(3-aminopropylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 130: 5-Phenyl-7-[3-(3-aminopropylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 131: 5-Phenyl-7-[4-(2-hydroxyethylsulfinyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 132: 5-Plhenyl-7-[3-(2-hydroxyethylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 193-195°C

Example 133: 5-Plhenyl-7-[4-(3-hydroxypropylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 134: 5-Plhenyl-7-[3-(3-hydroxypropylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 135: 5-Phenyl-7-[4-(2-aminoethylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 136: 5-Phenyl-7-[3-(2-aminoethylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 137: 5-Plhenyl-7-[4-(3-aminopropylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 138: 5-Plhenyl-7-[3-(3-aminopropylsulfonyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 139: N-(2-Hydroxysulfonylethyl)-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide

Example 140: 5-Plhenyl-7-[3-(2-hydroxysulfonylethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 141: 5-(4-Hydroxyphenyl)-7-(3-hydroxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 250-252ºC

Example 142: 5-(4-Hydroxyphenyl)-7-(3,4-methylenedioxyphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 258- 260ºC

Example 143: 5-(4-Hydroxyphenyl)-7-(3-hydroxymethylphenyl)-4-aminopyrrolo[2,3-d]pyrimidine, mp 234-236°C

Example 144: 5-(4-Hydroxyphenyl)-7-(3-chlorophenyl)-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 240-242ºC

Example 145: 5-(4-Hydroxyphenyl)-7-[3-(3-hydroxypropylaminomethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

or a salt thereof, for example the hydrochloride, amorphous foam

Example 146: 5-(4-Hydroxyphenyl)-7-[4-(2-hydroxyethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 222-226°C

Example 147: 5-(4-Hydroxyphenyl)-7-[4-(2-formyloxyethyl)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 209-211°C

Example 148: 5-Phenyl-7-[3-(2-formyloxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 136-138°C

Example 149: 5-Phenyl-7-[3-(2-N-morpholinoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 92-97ºC. The compound is obtained by reaction of 5-phenyl-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3- d]pyrimidine (see Example 108) and morpholine.

Example 150: 5-Phenyl-7-[3-(2-N,N-dimethylaminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 127-129ºC. The compound is obtained by the reaction of 5-phenyl-7-[3-(2-chloroethoxy)phenyl]-4- aminopyrrolo[2,3-d]pyrimidine (see Example 108) and dimethylamine.

Example 151: 5-(3-Hydroxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 245-247ºC

Example 152: 5-(4-Hydroxy-3-methylphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 215-218°C

Example 153: 5-(4-Hydroxv-3-methoxyphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 212-214°C

Example 154: 5-(4-Hydroxymethylphenyl)-7-phenyl-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 178-180ºC

Example 155: 5-(4-Hydroxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine 0.96 g of 5-(4-benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.22 g of sodium imidazole are heated to 60°C in 25 mL of DMF and the mixture is stirred for 14 h. The mixture is then cooled to RT and concentrated in a RE. The residue is treated with water, extracted three times with ethyl acetate and concentrated. The residue is recrystallized from ethanol/methylene chloride and the crystals are filtered off and washed with ethanol. After drying under HV, 5-(4-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a melting point of 183-186°C is obtained.

0.9 g of 5-(4-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 35 h in a hydrogen atmosphere at atmospheric pressure and about 40 °C in 40 mL of THF and 10 mL of ethanol in the presence of 0.15 g of 10% palladium/carbon. After filtration through Hyflo, the mixture is concentrated. The residue is chromatographed on silica gel (methylene chloride/methanol 9:1) and the fractions containing the product are combined and concentrated. The residue is slurried in ether and the crystals are filtered off and washed with ether. After drying under HV, 5-(4-hydroxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 217 - 220°C.

The output connection is made as follows:

(a) 3-(2-chloroethoxy)aniline: 60 g of 3-nitrophenol, 88 g of potassium carbonate and 178 mL of 1-bromo-2-chloroethane are boiled under reflux for 36 h in 800 mL of acetone together with 1.5 g of tetrabutylammonium bromide and 2.0 g of potassium iodide. The mixture is then cooled to RT and concentrated in a RE. The mixture is then treated with water, extracted three times with ethyl acetate and concentrated. The residue is chromatographed using methylene chloride and the fractions containing the product are concentrated. 1-(2-chloroethoxy)-3- nitrobenzene is obtained as an oil which can crystallize (mp 58-60ºC).

85.5 g of 1-(2-chloroethoxy)-3-nitrobenzene are hydrogenated in 800 ml of ethanol at normal pressure in a hydrogen atmosphere at RT for 4 h. After filtration through Celite and concentration in an RE, 3-(2-chloroethoxy)aniline is obtained as an oil (Rf = 0.4 silica gel, hexane / EA 2:1).

(b) 2'-(3-(2-chloroethoxy)phenylamino)-4-benzyloxyacetophenone: 16.1 g of 4-benzyloxyphenacyl bromide and 9.5 g of 3- (2-chloroethoxy)aniline are stirred at 50°C for 1.5 h in 150 mL of ethanol in the presence of 6.7 g of powdered Na₂CO₃. The mixture is then cooled and concentrated in a RE. The residue is partitioned between water and EA and the insoluble solid is filtered off to give a first portion of 2'-((3-(2-chloroethoxy)phenylamino)-4-benzyloxyacetophenone (mp 159-160°C). The biphasic mother liquor is extracted and the aqueous phase is re-extracted with EA. The combined organic phases are dried over Na₂SO₄ and concentrated. The residue is slurried with ether and the crystals are filtered off to give the second portion of 2'-(3-(2-chloroethoxy)phenylamino)-4-benzyloxyacetophenone. Additional 2'-(3-(2-chloroethoxy)phenylamino)-4-benzyloxyacetophenone (mp 157-159°C) is again obtained from the mother liquor by the addition of petroleum ether.

(c) 4-(4-Benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-amino-3-cyanopyrrole: 1.32 g of sodium is dissolved in 250 mL of ethanol and then first 4.12 g of malononitrile and then 20.6 g of 2'-(3-(2-chloroethoxy)phenylamino)-4-benzyloxyacetophenone suspended in 700 mL of THF are added at RT and the mixture is stirred at 50ºC for 15 h. After the addition of another 0.13 g of sodium and 0.4 g of malononitrile, the mixture is again stirred at 50ºC for 24 h. The mixture is then cooled and concentrated in a RE. The residue is slurried in EA/ether and the solid is filtered off and washed with EA/ether. One obtains 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-amino-3-cyanopyrrole with a melting point of 77-79ºC. The mother liquor is concentrated, the residue is dissolved in methylene chloride and the solution is filtered through a little silica gel. The mother liquor is concentrated, taken up in ether and a second batch of 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-amino-3-cyanopyrrole with a melting point of 84-87ºC crystallizes at 0ºC.

(d) 4-(4-Benzyloxyphenyl)-1-13-(2-chloroethoxy)phenyl-2-(n-ethoxyformimidato)-3-cyanopyrrole: 15.2 g of 4-(4- Benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-amino-3-cyanopyrrole and 0.5 mL of acetic anhydride are heated to 90 °C for 6.5 h in 200 mL of priethyl orthoformate. After cooling to RT, the mixture is concentrated in a RE. The residue is slurried in ether and the solid is filtered off and washed with ether. This gives 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-(n-ethoxyformimidato)-3-cyanopyrrole with a melting point of 169-171ºC.

(e) 4-(4-Benzyloxyphenyl)-1-3-(2-chloroethoxy)phenyl-2-(N-formamidino)-3-cyanopyrrole: 350 mL of ammonia in methanol (ca. 8%) and 13.5 g of 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-(N-ethoxyformimidato)-3-cyanopyrrole are stirred at RT for 12 h. 200 mL of methylene chloride and 100 mL of methanol in ammonia (ca. 8%) are then added and the solution is stirred for a further 60 h at RT. The mixture is then concentrated and the residue is slurried with methanol/ether, cooled to 0 °C and the crystals are filtered off. After filtration and drying under HV, 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]2-(N-formamidino)-3-cyanopyrrole is obtained with a melting point of 151-154ºC.

(f) 5-(4-Benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine: 0.1 g of sodium is dissolved in 200 mL of ethanol and then 10.5 g of 4-(4-benzyloxyphenyl)-1-[3-(2-chloroethoxy)phenyl]-2-(N-formamidino)-3-cyanopyrrole is added and the mixture is heated to 50ºC and stirred for 1 h. The mixture is then cooled and concentrated in a RE. The residue is treated with water, extracted three times with EA and concentrated. The residue is slurried in ether/EA, cooled to 0ºC and the solid is filtered off and washed with ether. 5-(4-Benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4- aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 146-148ºC.

Example 156: 5-(4-Hydroxyphenyl)-7-[4-(2-(1-imidazolyl]ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 4-(2-chloroethoxy)aniline, which is prepared from 4-nitrophenol and chlorobromomethane and a subsequent hydrogenation analogous to Example 155 by means of known processes, and 4-benzyloxyphenacyl bromide, which is prepared from 4-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide by means of known processes, 5-(4-benzyloxyphenyl)-7-[4-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a melting point of 188-190°C is obtained in an analogous reaction to Example 155.

0.8 g of 5-(4-benzyloxyphenyl)-7-[4-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.2 g of sodium imidazole are heated to 70°C in 30 ml of DMF and the mixture is stirred for 3 h. The mixture is then cooled to RT and treated with water, extracted three times with methylene chloride and concentrated. After chromatography on silica gel (methylene chloride/methanol 15:1) and crystallization from ether/methylene chloride, 5-(4-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 105-107°C.

0.5 g of 5-(4-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 22 h in a hydrogen atmosphere at normal pressure and about 50°C in 15 ml of THF in the presence of 0.1 g of 5% palladium I carbon. After filtration through Celite and crystallization by the addition of ether, 5-(4-hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 2 L0-212°C.

Example 157: 5-(3-Hydroxyphenyl)-7-[3-(2-(1-imidazole)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloroethoxy)aniline, which was prepared in Example 155 from 3-nitrophenol and chlorobromomethane with subsequent hydrogenation, and 3-benzyloxyphenacyl bromide, which was prepared by known methods from 3-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide, 5-(3-benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, Rf = 0.1 (Hex / EA 1 : 1, silica gel) is prepared by an analogous reaction.

2 g of 5-(3-benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Ex. 153) and 0.46 g of sodium imidazole in 45 mL of DMF are heated to 50 °C and the mixture is stirred for 15 h. The mixture is then cooled to RT and treated with water, extracted three times with ethyl acetate and concentrated. After chromatography on silica gel (methylene chloride / methanol with 5% about 5 N ammonia in methanol) 5-(3-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with an Rf = 0.4 is obtained (silica gel, methylene chloride / methanol with 5% about 5 N ammonia in methanol = 1).

1.85 g of 5-(3-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 80 h in a hydrogen atmosphere at normal pressure and about 40ºC in 40 ml of THIF in the presence of 0.4 g of 5% palladium / carbon. After filtration through Celite and crystallization from ethanol, 5- (3-hydroxyphenyl)-7-(3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a mp of 165-167ºC.

Example 158: 5-(3-Hydroxyphenyl)-7-[4-(2-N,N-dimethylaminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

and

Example 159: 5-(3-Hydroxyphenyl)-7-[4-(2-(2-hydroxyethy)amino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine.

Starting from 4-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 4-nitrophenol and chlorobromomethane with subsequent catalytic hydrogenation, and 3-benzyloxyphenacyl bromide, which was prepared from 3-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide using known processes, 5-(3-benzyloxyphenyl)-7-[4-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo- [2,3-d]pyrimidine, (Rf = 0.27, silica gel, hexane / EA 1:2) is obtained with an analogous reaction.

Analogously to Example 157, 2 g of 5-(3-benzyloxyphenyl)-7-[4-(2-chloroethoxy)phenyl]-4-aminopyrrolo- [2,3-d]pyrimidine (preparation see Example 157) and 0.38 ml of ethanolamine in 20 ml of DMF are heated to 50°C for 15 h with stirring and, after the addition of 0.8 ml of ethanolamine, heated again to 70°C for 15 h. The mixture is then cooled to RT and treated with water, extracted three times with EA and concentrated. After chromatography on silica gel (methylene chloride/methanol with 5% ca. 5 N ammonia in methanol 9:1), 5- (3-benzyloxyphenyl)-7-[4-(2-N,N-dimethylaminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Rf = 0.3) and then 5-(3-benzyloxyphenyl)-7-[4-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Rf = 0.12) eluted first.

A catalytic hydrogenation of 5-(3-benzyloxyphenyl)-7-[4-(2-N,N-dimethylaminoethoxy)phenyl]-4- aminopyrrolo[2,3-d]pyrimidine analogously to Example 151 in TIfF in the presence of 5% Pd/C gives, after work-up, 5-(3-hydroxyphenyl)-7-[4-(2-N,N-dimethylaminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a mp of 224-226 °C.

A catalytic hydrogenation of 5-(3-benzyloxyphenyl)-7-[4-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4- aminopyrrolo[2,3-d]pyrimidine analogously to Example 151 in THF in the presence of 5% Pd/C gives, after work-up, 5-(3-hydroxyphenyl)-7-[4-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a mp of 200-202 °C.

For example, 5-(3-hydroxyphenyl)-7-[4-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Example 159) can also be prepared from 5-(3-benzyloxyphenyl)-7-[4-(2-chloroethoxy)phenyl]-4-aminopyrrolo(2,3- d]pyrimidine by heating in an excess of ethanolamine without solvent and subsequent catalytic hydrogenation.

Example 160: 5-(3-Hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(3-chloro-1-propoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and 1-bromo-3-chloropropane with subsequent catalytic hydrogenation, and 3-benzyloxyphenacyl bromide, which was prepared by known methods from 3-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide, 5-(3-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Rf = = 0.2, silica gel, hexane / EA 1:1) is prepared with an analogous reaction.

1.5 g of 5-(3-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.33 g of sodium imidazole in 30 mL of DMF are heated to 50ºC and the mixture is stirred overnight. It is then cooled to RT, the solvent is evaporated in a RE and the mixture is treated with water, extracted three times with ethyl acetate and concentrated. 5-(3-benzyloxyphenyl)-7-[3-(3-(1- imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained (Rf = 0.44 silica gel, methylene chloride / methanol with 5% about 5 N ammonia in methanol = 9:1).

1.35 g of 5-(3-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 16 h in a hydrogen atmosphere at normal pressure and about 40°C in 30 ml of methanol in the presence of 0.3 g of 5% palladium/carbon. After filtration through Celite, the solvent is evaporated and the residue is slurried in ether, filtered, re-slurried in EA, filtered and dried. 5-(3-hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a mp of 120-122°C.

Analogously to Examples 158 and 159, starting from 5-(3-benzyloxyphenyl)-7-[3-(3-chloro-1- propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (see Example 160), the following compounds are obtained in two steps:

Example 161: 5-(3-Hydroxyphenyl)-7-[3-(3-N,N-dimethylaminopropoxy)phenyl-4-aminopyrrolo[2,3-d]pyrimidine, mp 169-172°C Example 162: 5-(3-Hydroxyphenyl)-7-[3-(3-(2-hydroxyethylamino)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, mp 124-126°C

5-(3-Hydroxyphenyl)-7-[3-(3-(2-hydroxyethylamino)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Example 162) can also be prepared, for example, from 5-(3-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4- aminopyrrolo[2,3-d]pyrimidine by heating in an excess of ethanolamine without solvent and subsequent catalytic hydrogenation.

Example 163: 5-(3-Hydroxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine,

2.0 g of 5-(3-benzyloxyphenyl)-7-[4-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (see Examples 158/159) and 0.46 g of sodium imidazole are heated to 50 °C in 40 mL of DMF and the mixture is stirred for 15 h. The mixture is then cooled to RT and treated with water, extracted three times with ethyl acetate and concentrated. The solvent is evaporated in a RE and the mixture is treated with water, extracted three times with EA and concentrated. The residue is suspended in ether to give, after filtration and drying under UV, 5-(3-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Rf = 0.13 silica gel, methylene chloride/methanol with 5% ca. 5 N ammonia in methanol 9:1).

1.7 g of 5-(3-benzyloxyphenyl)-7-[4-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 24 h in a hydrogen atmosphere at normal pressure and about 40ºC in 40 ml of methanol in the presence of 0.4 g of 5% palladium/carbon. After filtration through Celite and chromatography on silica gel (methylene chloride/methanol with 5% about 5 N ammonia in methanol 9:1) one obtains 5-(3-hydroxyphenyl)-7-[4- (2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a mp of 221-223ºC.

Example 164: 5-(4-Hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(3-chloro-1-propoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and 1-bromo-3-chloropropane with subsequent catalytic hydrogenation, and 4-benzyloxyphenacyl bromide, which was prepared by known methods from 4-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide, 5-(4-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 143-146°C, is prepared by an analogous reaction.

1.0 g of 5-(4-benzyloxyphenyl)-7-[3-(3-chloro-1-propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.22 g of sodium imidazole are heated to 60°C in 25 ml of DMF and the mixture is stirred for 6 h. The mixture is then cooled to RT, treated with water, extracted three times with ethyl acetate and concentrated. The residue is suspended in ethyl acetate and after filtration and drying under HV 5-(4-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 144-147°C.

0.9 g of 5-(4-benzyloxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 20 h in a hydrogen atmosphere at normal pressure and about 40°C in 40 ml of methanol in the presence of 0.15 g of 10% palladium/carbon. After filtration through Celite and chromatography of the residue on silica gel (methylene chloride/methanol 9:1), 5-(4-hydroxyphenyl)-7-[3-(3-(1-imidazolyl)propoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Rf = 0.2 silica gel, methylene chloride/methanol 9:1) is obtained.

Example 165: 5-(4-Hydroxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 4-benzyloxy-3-methylphenacyl bromide, which was prepared by known methods from 4-hydroxy-3-methylacetophenone by benzylation and bromination with bromine or copper bromide, 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]- 4-aminopyrrolo[2,3-d]pyrimidine, m.p. 133-135°C, is prepared by an analogous reaction.

0.7 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.2 g of sodium imidazole are heated to 80ºC in 30 mL of DMF and the mixture is stirred for 5 h. The mixture is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4- benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 158-160ºC.

0.4 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 10 h in a hydrogen atmosphere at normal pressure and about 40ºC in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium / carbon. After filtration through Celite and crystallization of the residue from methylene chloride gives 5-(4-hydroxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a melting point of 202-204ºC.

Example 166: 5-(4-Hydroxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 4-benzyloxy-3-methylphenacyl bromide, which was prepared by known methods from 4-hydroxy-3-methylacetophenone by benzylation and bromination with bromine or copper bromide, 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)- phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 168-169°C, is prepared by an analogous reaction.

0.8 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.2 g of sodium imidazole are heated to 80°C in 30 ml of DMF and the mixture is stirred for 5 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4-benzyloxy-3- methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 122-124°C.

0.6 g of 5-(4-benzyloxy-3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 6 h in a hydrogen atmosphere at normal pressure and about 50°C in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methoxyphenyl)-7-[3-(2-(1- imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 190°C.

Example 167: 5-(3-Hydroxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 4-benzyloxy-3-methylphenacyl bromide, which was prepared by known methods from 4-methoxy-3-hydroxyacetophenone by benzylation and bromination with bromine or copper bromide, 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]4-aminopyrrolo[2,3-d]pyrimidine, m.p. 170°C, is obtained.

1.1 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.3 g of sodium imidazole are heated to 85ºC in 30 mL of DMF and the mixture is stirred for 8 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(3-benzyloxy-4- methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 150ºC. 0.75 g of 5-(3-benzyloxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 12 h in a hydrogen atmosphere at normal pressure and about 50°C in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 10% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(3-hydroxy-4-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a melting point of 205-207°C.

Example 168: 5-(4-Hydroxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 4-benzyloxy-3,5-dimethylphenacyl bromide, which was prepared by known methods from 4-hydroxy-3,5-dimethylacetophenone by benzylation and bromination with bromine or copper bromide, there is obtained 5-(4-benzyloxy-3,5-dimethylphenyl)-7-[3-(2- chloro-1-ethoxy)plienyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 188-190°C.

0.45 g of 5-(4-benzyloxy-3,5-dimethylphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.11 g of sodium imidazole are heated to 85°C in 10 ml of DMF and the mixture is stirred for 8 h. It is then cooled to RT and concentrated. The residue is treated with water and extracted with methylene chloride and the organic phases are dried and concentrated. After crystallization of the residue from methylene chloride/ether, 5-(4-hydroxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)- ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 100°C.

0.35 g of 5-(4-benzyloxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine are hydrogenated for 2 h in a hydrogen atmosphere at normal pressure and about 50°C in 15 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 10% palladium/carbon. After filtration through Celite and chromatography on silica gel using methylene chloride/methanol 10:1, 5-(4-hydroxy-3,5-dimethylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine with a melting point of 150-152°C is obtained after crystallization from methylene chloride.

Example 169: 5-(3-Methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 3-methoxyphenacyl bromide, 5-(methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained in an analogous manner, m.p. 160°C.

0.8 g of 5-(3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.24 g of sodium imidazole are heated to 80°C in 20 ml of DMF and stirred for 5 h. The mixture is then cooled to RT, treated with water, extracted three times with methylene chloride and concentrated. After chromatography on silica gel using methylene chloride/methanol 15:2 and crystallization from ether/methylene chloride, 5-(3-methoxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a m.p. of 138-140°C.

Example 170: 5-(3-Chlorophenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Starting from 3-(2-chloro-1-ethoxy)aniline, which was prepared analogously to Example 155 from 3-nitrophenol and chlorobromoethane with subsequent catalytic hydrogenation, and 3-chlorophenacyl bromide, 5-(3-chlorophenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 175- 177°C, is obtained in an analogous manner.

0.4 g of 5-(3-methoxyphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine and 0.12 g of sodium imidazole are heated to 80°C in 10 ml of DMF and the mixture is stirred for 5.5 h. The mixture is then cooled to RT, treated with water, extracted three times with methylene chloride and concentrated. After chromatography on silica gel using methylene chloride/methanol 15:1 and crystallization from ether/methylene chloride, 5-(3-chlorophenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine is obtained with a mp of 125-127°C.

Example 171: 5-(4-Hydroxyphenyl)-7-[3-(2-methoxyethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine, m.p. 103- 112ºC. The compound is prepared analogously to Example 155. The starting material used is 3-(2- methoxyethoxy)aniline. This is prepared by the reaction of 3-fluoronitrobenzene with the sodium salt of 2-methoxyethanol followed by reduction of the nitro group on the amino group.

The following compounds are also prepared analogously to the previous examples:

Example 172: 5-(3-Hydroxyphenyl)-7-[4-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 173: 5-(3-Hydroxyphenyl)-7-[3-(2-aminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 174: 5-(4-Methoxyphenyl)-7-[3-(2-(2-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 175: 5-(:3-Methoxyphenyl)-7-[3-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3d]pyrimidine

Example 176: 5-(:3-Hydroxyphenyl)-7-[3-(2-N,N-dimethylaminoethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Example 177: 5-(:3-Hydroxyphenyl)-7-[3-(2-(2-hydroxyethylamino)ethoxy)phenyl]4-aminopyrrolo[2,3-d]pyrimidine

Example 178: 5-(3-Methoxyphenyl)-7-[4-(2-(2-hydroxyethylamino)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine

Examples A-B: Pharmaceutical compositions Example A: Tablets each containing 50 mg of active ingredient: Composition 10 000 tablets

Active ingredient 500.0 g

Lactose 500.0 g

Potato starch 352.0 g

Gelatin g,0

Talc 60.0

Magnesium stearate 10.0

Silicon dioxide (highly dispersed) 20.0

Ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potato starch and the mixture is moistened with the ethanolic solution of gelatin and granulated through a sieve. After drying, the rest of the potato starch, magnesium stearate, talc and silicon dioxide are mixed and the mixture is pressed to form tablets, each weighing 145 mg and containing 50 mg of active ingredient, which can, if desired, be provided with predetermined breaking points for a finer adjustment of the dose.

Example B: Film-coated tablets, each containing 100 mg of active ingredient: Composition 1000 film-coated tablets

Active ingredient 100.0

Lactose 100.0

Corn starch 70.0 g

Talc 8.5

Calcium stearate 1.5

Hvdroxypro lmeth lcellulose 2.36 g

Shellac 0.64

Water q.s.

Dichloromethane q.s.

The active ingredient, lactose and 40 g of corn starch are mixed. The mixture is moistened with a paste prepared from 15 g of corn starch and water (with heating) and granulated. The granules are dried and the rest of the corn starch, talc and calcium stearate are mixed with the granules. The mixture is pressed to form tablets (weight: 280 mg each) and these are coated with a solution of hydroxypropylmethylcellulose and shellac in dichloromethane (final weight of film-coated tablets: 283 mg each).

Claims (12)

1. Compound of formula I wherein R1; represents phenyl which is unsubstituted or substituted by one or two substituents selected from the group consisting of lower alkyl, halogen lower alkyl, (hydroxy- or lower alkanoyloxy) lower alkyl, lower alkoxy lower alkyl, (hydroxy-, lower alkoxy or lower alkanoyloxy) lower alkoxy lower alkyl, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino) lower alkoxy lower alkyl, (amino- or lower alkylamino) lower alkyl, lower alkylamino lower alkyl, di-lower alkylamino lower alkyl, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl) lower alkyl, (imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl or pyrrolyl) lower alkyl, (hydroxy-, lower alkoxy- or lower alkanoyloxy) lower alkylamino lower alkyl, (Amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkylamino-lower alkyl, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkylamino-lower alkyl, (imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkylamino-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkyl-(thio-, sullinyl- or sulfonyl)-lower alkyl, (amino-, lower alkylamino- di-lower alkylamino- or lower alkanoylamino)-lower alkyl-(thio-, sulfinyl- or sulfonyl)- lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, aminocarbonyl-lower alkyl, N-lower alkylaminocarbonyllower alkyl, N,N-dilower alkylaminocarbonyllower alkyl, hydroxyl, lower alkoxy, lower alkanoyloxy, C₁-C₃ Alkylenedioxy, phenyl lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkoxy, (amino- or lower alkanoylamino)-lower alkoxy, lower alkylamino lower alkoxy, di-lower alkylamino lower alkoxy, (piperidinyl- piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkoxy, (imidazolyl- triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkylamino lower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino or lower alkanoylamino)-lower alkylamino lower alkoxy, (piperidinyl-, piperazinyl-, morpholinyl or pyrrolidinyl)-lower alkylamino lower alkoxy, (Imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkylamino-lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkoxy-lower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkoxy-lower alkoxy, (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkoxy, (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkyl(thio-, sulfinyl- or sulfonyl)-lower alkoxy, hydroxysulfonyllower alkoxy, carboxylower alkoxy, lower alkoxycarbonyllower alkoxy, aminocarbonyllower alkoxy, N-lower alkylaminocarbonyl lower alkoxy, N,N-di-lower alkyl amino carbonyl rueder alkoxy, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolyl, mercapto, lower alkyl-(thio, suffin yl or sulfonyl), (hydroxy, lower alkoxy or lower alkanoyloxy)- lower alkyl-(thio, sulfinyl or sulfonyl), (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkyl-(thio, sulfinyl or sulfonyl), (hydroxy-, lower alkoxy- or lower alkanoyloxy)lower alkoxylower alkyl-(thio, sulfinyl or sulfonyl), (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkoxylower alkyl-(thio, sulfinyl or sulfonyl), (hydroxy-, lower alkoxy- or lower alkanoyloxy)-lower alkylaminolower alkyl(thio, sulfinyl or sulfonyl), (amino-, lower alkylamino-, di-lower alkylamino- or lower alkanoylamino)-lower alkylaminolower alkyl-(thio, suitinyl or sulfonyl), carboxylower alkylthio. Lower alkoxycarbonyllower alkylthio, aminocarbonyllower alkylthio, N-lower alkylaminocarbonyllower alkylthio. N,N-dilower alkylaminocarbonyllower alkylthio, halogen, carboxyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylanocarbonyl. N-(hydroxy-, lower-alkoxy- or lower-alkanoyloxy)-lower alkyl]-aminocarbonyl, N-[(amino-, lower-allcylamino-, di-lower-alkylamino- or lower-alkanoylamino)-lower alkyl]-aminocarbonyl, N-[(piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower allcyl]-aminocarbonyl, N -[(imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower alkyl]-aminocarbonyl, N-(hydroxysulfonyl-lower alkyl)-aminocarbonyl, N,N-di-lower alkylaminocarbonyl, cyano, amidino, formamidino and guanidino, R₂ represents hydrogen, lower alkyl or halogen, R₃ is phenyl which is unsubstituted or substituted by one, two or three substituents from the group consisting of lower alkyl, hydroxy-lower alkyl, phenyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, C1-C₃ alkylenedioxy, cyano and halogen, and "lower" stands for a radical with up to and including 7 carbon atoms, with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl , or a salt thereof. 2. A compound of formula I according to claim 1, wherein R1; represents phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkanoyloxy lower alkyl, halogen lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, di lower alkylamino lower alkyl, (piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl) lower alkyl, (imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl) lower alkyl, hydroxy lower alkylamino lower alkyl, amino lower alkylamino lower alkyl, (piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl) lower alkylamino lower alkyl, (imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrrolyl) lower alkylamino lower alkyl, mercapto lower alkyl, lower alkyl (thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxylower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, aminolower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxyl, lower alkoxy, C₁-C₃ alkylenedioxy, phenyllower alkoxy, hydroxylower alkoxy, lower alkoxylower alkoxy, lower alkanoyloxylower alkoxy, aminolower alkoxy, lower alkylaminolower alkoxy, dilower alkylaminolower alkoxy, (piperidinyl- piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkoxy, (imidazolyl- triazolyl-, pyridyl-, pyrimidinyl- or Pyrrolyl)-lower alkoxy, hydroxy-lower alkylaminone-lower alkoxy, amino-lower alkylaminone-lower alkoxy, (piperidinyl-, piperazinyl-, morpholinyl- or pyrrrolidinyl)-lower-alkylaminone-lower alkoxy, (imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl)-lower allcylaminone-lower alkoxy, hydroxys ulfonyl-lower alkoxy, amino, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrrolyl, mercapto, lower alkyl-(thio, sulfinyl or sulfonyl), hydroxy-lower alkyl-(thio, sulfinyl or sulfonyl), amino-lower alkyl-(thio, sulfinyl or sulfonyl), halogen, carboxyl, lower alkoxycarbonyl, aminocarbonyl, N-lower alkylaminocarbonyl, N-(hydroxylower alkyl)-aminocarbonyl, N-(amin lower alkyl)-aminocarbonyl, N-[(piperidinyl-, piperazinyl-, morpholinyl- or pyrrolidinyl)-lower alkyl]-aminocarbonyl, N-[(imidazolyl-, triazolyl-, pyridyl-, pyrimidinyl- or pyrrolyl) -lower alkyl]-aminocarbonyl, N-(hydroxysulfonyl-lower alkyl)-aminocarbonyl, N,N-di-lower alkylaminocarbonyl and cyano, and R₂ and R₃ are as defined in claim 1, with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R₁ represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl , or a pharmaceutically acceptable salt thereof. 3. A compound of formula I according to claim 1, wherein R₁ is phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, hydroxylower alkyl, halogenlower alkyl, aminolower alkyl, lower alkylaminolower alkyl, dilower alkylaminolower alkyl, (pyrimidinyl-, piperazinyl-, morpholinyl)-lower alkyl, (imidazolyl-, triazolyl-, pyridyl- or pyrrolyl)-lower alkyl, hydroxylower alkylaminolower alkyl, aminolower alkylanunolower alkyl, (pyrimidinyl-, piperazinyl- or morpholinyl)-lower alkylaminolower alkyl, (imidazolyl-, triazolyl-, pyridyl-, or pyrrolyl)-lower alkylaminolower alkyl, mercaptolower alkyl, lower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxylower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, aminolower alkyl-(thio-, sulfinyl- or sulfonyl)-lower alkyl, hydroxyl, lower alkoxy, C₁-C₃ Alkylendioxy, Phenylniederalkoxy, Hydroxyniederalkoxy, Aminoniederalkoxy, Niederalkylaminoniederalkoxy, Diniederalkylaminoniederalkoxy, (Pyrimidinyl-, Piperazinyl- oder Morpholinyl)-niederalkoxy, (Imidazolyl- Triazolyl-, Pyridyl- oder Pyrrolyl)-niederalkoxy, Hydroxyniederalkylaminoniederalkoxy, Anninoniederalkylaminoniederalkoxy, (Pyrimidinyl-, Piperazinyl- oder Morpholinyl)-niederalkylaminoniederalkoxy, (Imidazolyl-, Triazolyl-, Pyridyl- oder Pyrrolyl)-niederallcylaminoniederalkoxy, Hydroxysulfonylniederalkoxy, Arnino, Pyrimidinyl, Piperazinyl, Morpholinyl, Imidazolyl, Triazolyl, Pyridyl, Pyrrolyl, Mercapto, Niederalkyl-(thio, sulfinyl oder sulfonyl), Hydroxyniederalkyl-(thio, sulfinyl oder sulfonyl), Aminoniederalkyl- (thio, sulfinyl oder sulfonyl), Halogen, Carboxyl, Niederalkoxycarbonyl, Aminocarbonyl, N-Niederalkylaminocarbonyl, N-(Hydroxyniederallcyl)-aminocarbonyl, N-(Aminoniederalkyl)-aminocarbonyl, N-[(Pyrimidinyl-, Piperazinyl- oder Morpholinyl)-niederalkyl]-aminocarbonyl, N-[(Imidazolyl-, Triazolyl-, Pyridyl- oder Pyrrolyl)-niederalkyl]-aminocarbonyl, N-(Hydroxysulfonylniederalkyl)-aminocarbonyl, N,N-Diniederalkylaminocarbonyl und Cyano, und R₂ is as defined in claim 1, and R₃ and R₃' are phenyl which is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, phenyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, C₁-C₃ alkylenedioxy, cyano and halogen, with the proviso that R₃ does not represent phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl if R₂ represents hydrogen and R₁ represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl, or a pharmaceutically acceptable salt thereof. 4. N-(2-hydroxyethyl)-3-(S-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzamide according to claim 1 or a pharmaceutically acceptable salt thereof. 5. Use of a compound of formula I wherein R₁, R₂ and R₃ are as defined in claim 1, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of diseases responsive to inhibition of the activity of protein tyrosine kinase pp60c-src. 6. Use according to claim 5, characterized in that a compound of formula I is used, wherein R₁ is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl or 4-iodophenyl, R₂ is hydrogen and R₃ is phenyl, 4-methoxyphenyl or 4-chlorophenyl, or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier. 8. A compound according to any one of claims 1 to 4 for use in a method for therapeutic treatment of the animal or human body. 9. A compound according to any one of claims 1 to 4 for use in the treatment of diseases responsive to inhibition of the activity of the protein tyrosine kinase pp60c-src. 10. Use of a compound according to any one of claims 1 to 4 for the preparation of pharmaceutical compositions. 11. Use of a compound according to any one of claims 1 to 4 for the preparation of pharmaceutical compositions for the treatment of diseases which respond to the inhibition of the activity of the protein tyrosine kinase pp60c-src. 12. . A process for preparing a compound of formula I according to claim 1, wherein (a) a compound of formula II undergoes a ring closure reaction to synthesize the pyrimidine ring, or (b) a compound of formula III undergoes a ring closure reaction to synthesize the pyrimidine ring, or (c) a compound of formula IV if desired, after a temporary activation, is reacted with an aminating agent, and, if desired, a compound of formula I is converted into another compound of formula I and/or, if desired, a resulting salt is converted into the free compound or into another salt and/or, if desired, a resulting free compound of formula I with salt-forming properties is converted into a salt.